WO2002032920A2 - Modified nucleosides for treatment of viral infections and abnormal cellular proliferation - Google Patents
Modified nucleosides for treatment of viral infections and abnormal cellular proliferation Download PDFInfo
- Publication number
- WO2002032920A2 WO2002032920A2 PCT/US2001/046113 US0146113W WO0232920A2 WO 2002032920 A2 WO2002032920 A2 WO 2002032920A2 US 0146113 W US0146113 W US 0146113W WO 0232920 A2 WO0232920 A2 WO 0232920A2
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- pharmaceutically acceptable
- nucleoside
- acceptable salt
- treatment
- deoxy
- Prior art date
Links
- 230000002159 abnormal effect Effects 0.000 title claims abstract description 58
- 230000004663 cell proliferation Effects 0.000 title claims abstract description 56
- 238000011282 treatment Methods 0.000 title claims description 163
- 230000009385 viral infection Effects 0.000 title claims description 39
- 208000036142 Viral infection Diseases 0.000 title claims description 36
- 125000003835 nucleoside group Chemical group 0.000 title description 95
- 239000002777 nucleoside Substances 0.000 claims abstract description 349
- 150000003833 nucleoside derivatives Chemical class 0.000 claims abstract description 133
- 150000003839 salts Chemical class 0.000 claims abstract description 133
- 238000000034 method Methods 0.000 claims abstract description 132
- 241000710781 Flaviviridae Species 0.000 claims abstract description 48
- 241000712464 Orthomyxoviridae Species 0.000 claims abstract description 43
- 241000711504 Paramyxoviridae Species 0.000 claims abstract description 42
- 150000001875 compounds Chemical class 0.000 claims description 151
- -1 monophosphate ester Chemical class 0.000 claims description 145
- 239000001257 hydrogen Substances 0.000 claims description 84
- 229910052739 hydrogen Inorganic materials 0.000 claims description 84
- 238000011321 prophylaxis Methods 0.000 claims description 52
- 125000000217 alkyl group Chemical group 0.000 claims description 46
- 150000002431 hydrogen Chemical class 0.000 claims description 39
- 229910052794 bromium Inorganic materials 0.000 claims description 33
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 32
- 239000003814 drug Substances 0.000 claims description 27
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 27
- 229910052740 iodine Inorganic materials 0.000 claims description 26
- 125000003118 aryl group Chemical group 0.000 claims description 25
- 229910052801 chlorine Inorganic materials 0.000 claims description 25
- 230000001747 exhibiting effect Effects 0.000 claims description 25
- 229910052731 fluorine Inorganic materials 0.000 claims description 23
- 229910052736 halogen Inorganic materials 0.000 claims description 20
- 150000002367 halogens Chemical group 0.000 claims description 20
- 239000003937 drug carrier Substances 0.000 claims description 18
- 208000010710 hepatitis C virus infection Diseases 0.000 claims description 18
- 239000001226 triphosphate Substances 0.000 claims description 18
- 239000001177 diphosphate Substances 0.000 claims description 16
- 235000011180 diphosphates Nutrition 0.000 claims description 16
- 238000004519 manufacturing process Methods 0.000 claims description 16
- 125000002252 acyl group Chemical group 0.000 claims description 15
- 235000011178 triphosphate Nutrition 0.000 claims description 15
- 125000003342 alkenyl group Chemical group 0.000 claims description 14
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 14
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 14
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims description 14
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 14
- 229910052717 sulfur Inorganic materials 0.000 claims description 13
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 12
- 229910052760 oxygen Inorganic materials 0.000 claims description 12
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 11
- CBOIHMRHGLHBPB-UHFFFAOYSA-N hydroxymethyl Chemical compound O[CH2] CBOIHMRHGLHBPB-UHFFFAOYSA-N 0.000 claims description 10
- 150000001413 amino acids Chemical class 0.000 claims description 8
- XPPKVPWEQAFLFU-UHFFFAOYSA-J diphosphate(4-) Chemical compound [O-]P([O-])(=O)OP([O-])([O-])=O XPPKVPWEQAFLFU-UHFFFAOYSA-J 0.000 claims description 8
- 150000004712 monophosphates Chemical class 0.000 claims description 8
- 150000003904 phospholipids Chemical class 0.000 claims description 8
- UNXRWKVEANCORM-UHFFFAOYSA-N triphosphoric acid Chemical compound OP(O)(=O)OP(O)(=O)OP(O)(O)=O UNXRWKVEANCORM-UHFFFAOYSA-N 0.000 claims description 8
- XXJGBENTLXFVFI-UHFFFAOYSA-N 1-amino-methylene Chemical compound N[CH2] XXJGBENTLXFVFI-UHFFFAOYSA-N 0.000 claims description 6
- 229910014033 C-OH Inorganic materials 0.000 claims description 6
- 229910014570 C—OH Inorganic materials 0.000 claims description 6
- 229910052698 phosphorus Inorganic materials 0.000 claims description 6
- 125000002877 alkyl aryl group Chemical group 0.000 claims description 5
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 5
- 125000000304 alkynyl group Chemical group 0.000 claims description 3
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 3
- 229910052799 carbon Inorganic materials 0.000 claims description 3
- 229910052711 selenium Inorganic materials 0.000 claims description 3
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 3
- 239000000203 mixture Substances 0.000 abstract description 100
- 229940002612 prodrug Drugs 0.000 abstract description 72
- 239000000651 prodrug Substances 0.000 abstract description 72
- 241000700605 Viruses Species 0.000 abstract description 64
- 241000710780 Bovine viral diarrhea virus 1 Species 0.000 abstract description 35
- 208000037797 influenza A Diseases 0.000 abstract description 31
- 208000015181 infectious disease Diseases 0.000 abstract description 29
- 239000000523 sample Substances 0.000 abstract description 26
- 230000003612 virological effect Effects 0.000 abstract description 26
- 208000037798 influenza B Diseases 0.000 abstract description 18
- 230000008569 process Effects 0.000 abstract description 16
- 241001465754 Metazoa Species 0.000 abstract description 14
- 238000003753 real-time PCR Methods 0.000 abstract description 9
- 241000710886 West Nile virus Species 0.000 abstract description 5
- PPBOKXIGFIBOGK-BDTUAEFFSA-N bvdv Chemical compound C([C@@H](C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)C(C)C)[C@@H](C)CC)C1=CN=CN1 PPBOKXIGFIBOGK-BDTUAEFFSA-N 0.000 abstract 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 89
- OPTASPLRGRRNAP-UHFFFAOYSA-N cytosine Chemical class NC=1C=CNC(=O)N=1 OPTASPLRGRRNAP-UHFFFAOYSA-N 0.000 description 89
- ISAKRJDGNUQOIC-UHFFFAOYSA-N Uracil Natural products O=C1C=CNC(=O)N1 ISAKRJDGNUQOIC-UHFFFAOYSA-N 0.000 description 88
- 210000004027 cell Anatomy 0.000 description 78
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 75
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 69
- DRTQHJPVMGBUCF-XVFCMESISA-N Uridine Chemical group O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C=C1 DRTQHJPVMGBUCF-XVFCMESISA-N 0.000 description 69
- 239000000243 solution Substances 0.000 description 57
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 56
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 56
- 229940104302 cytosine Drugs 0.000 description 50
- 241000711549 Hepacivirus C Species 0.000 description 48
- 229940035893 uracil Drugs 0.000 description 48
- 229940045145 uridine Drugs 0.000 description 47
- 241000725643 Respiratory syncytial virus Species 0.000 description 39
- 230000000840 anti-viral effect Effects 0.000 description 39
- 239000002585 base Substances 0.000 description 38
- 238000006243 chemical reaction Methods 0.000 description 38
- 239000000460 chlorine Substances 0.000 description 36
- 210000000481 breast Anatomy 0.000 description 35
- DRTQHJPVMGBUCF-PSQAKQOGSA-N beta-L-uridine Natural products O[C@H]1[C@@H](O)[C@H](CO)O[C@@H]1N1C(=O)NC(=O)C=C1 DRTQHJPVMGBUCF-PSQAKQOGSA-N 0.000 description 34
- DRTQHJPVMGBUCF-UHFFFAOYSA-N uracil arabinoside Natural products OC1C(O)C(CO)OC1N1C(=O)NC(=O)C=C1 DRTQHJPVMGBUCF-UHFFFAOYSA-N 0.000 description 34
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 33
- 230000015572 biosynthetic process Effects 0.000 description 31
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 31
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 30
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 30
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 29
- 208000017604 Hodgkin disease Diseases 0.000 description 28
- 208000010747 Hodgkins lymphoma Diseases 0.000 description 28
- 239000003795 chemical substances by application Substances 0.000 description 28
- 238000003786 synthesis reaction Methods 0.000 description 28
- 208000015914 Non-Hodgkin lymphomas Diseases 0.000 description 26
- 238000012360 testing method Methods 0.000 description 26
- KDCGOANMDULRCW-UHFFFAOYSA-N Purine Natural products N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 25
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 24
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 23
- 238000003757 reverse transcription PCR Methods 0.000 description 23
- 229960002949 fluorouracil Drugs 0.000 description 22
- 230000000670 limiting effect Effects 0.000 description 22
- 210000004072 lung Anatomy 0.000 description 22
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 21
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 21
- 229940079593 drug Drugs 0.000 description 20
- 206010022000 influenza Diseases 0.000 description 20
- 239000002773 nucleotide Substances 0.000 description 20
- 230000009467 reduction Effects 0.000 description 20
- 239000002904 solvent Substances 0.000 description 20
- 235000000346 sugar Nutrition 0.000 description 20
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 19
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 19
- 229960000583 acetic acid Drugs 0.000 description 19
- 125000003729 nucleotide group Chemical group 0.000 description 19
- 239000000047 product Substances 0.000 description 19
- 239000002212 purine nucleoside Substances 0.000 description 19
- 229910052938 sodium sulfate Inorganic materials 0.000 description 19
- 238000005160 1H NMR spectroscopy Methods 0.000 description 18
- 208000024893 Acute lymphoblastic leukemia Diseases 0.000 description 18
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 18
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 18
- WFDIJRYMOXRFFG-UHFFFAOYSA-N acetic acid anhydride Natural products CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 18
- 230000000694 effects Effects 0.000 description 18
- 235000011152 sodium sulphate Nutrition 0.000 description 18
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 17
- 239000002253 acid Substances 0.000 description 17
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 17
- 238000002360 preparation method Methods 0.000 description 17
- 241000282412 Homo Species 0.000 description 16
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 16
- 230000005764 inhibitory process Effects 0.000 description 16
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 16
- 210000001550 testis Anatomy 0.000 description 16
- 208000035475 disorder Diseases 0.000 description 15
- 239000003112 inhibitor Substances 0.000 description 15
- RWQNBRDOKXIBIV-UHFFFAOYSA-N thymine Chemical class CC1=CNC(=O)NC1=O RWQNBRDOKXIBIV-UHFFFAOYSA-N 0.000 description 15
- 208000031261 Acute myeloid leukaemia Diseases 0.000 description 14
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 14
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 14
- 206010028980 Neoplasm Diseases 0.000 description 14
- IWUCXVSUMQZMFG-AFCXAGJDSA-N Ribavirin Chemical compound N1=C(C(=O)N)N=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 IWUCXVSUMQZMFG-AFCXAGJDSA-N 0.000 description 14
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 14
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 14
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 14
- 201000010099 disease Diseases 0.000 description 14
- 210000001672 ovary Anatomy 0.000 description 14
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 14
- 108090000623 proteins and genes Proteins 0.000 description 14
- HZCAHMRRMINHDJ-DBRKOABJSA-N ribavirin Natural products O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1N=CN=C1 HZCAHMRRMINHDJ-DBRKOABJSA-N 0.000 description 14
- 229960000329 ribavirin Drugs 0.000 description 14
- 239000000741 silica gel Substances 0.000 description 14
- 229910002027 silica gel Inorganic materials 0.000 description 14
- 229960005486 vaccine Drugs 0.000 description 14
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 13
- 201000011510 cancer Diseases 0.000 description 13
- 238000009833 condensation Methods 0.000 description 13
- 230000005494 condensation Effects 0.000 description 13
- 230000000120 cytopathologic effect Effects 0.000 description 13
- 229960004413 flucytosine Drugs 0.000 description 13
- 230000004048 modification Effects 0.000 description 13
- 238000012986 modification Methods 0.000 description 13
- 239000012044 organic layer Substances 0.000 description 13
- 230000010076 replication Effects 0.000 description 13
- ZHHOTKZTEUZTHX-SHYZEUOFSA-N 4-amino-1-[(2r,3r,5s)-3-hydroxy-5-(hydroxymethyl)oxolan-2-yl]pyrimidin-2-one Chemical class O=C1N=C(N)C=CN1[C@H]1[C@H](O)C[C@@H](CO)O1 ZHHOTKZTEUZTHX-SHYZEUOFSA-N 0.000 description 12
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 12
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 12
- 230000015556 catabolic process Effects 0.000 description 12
- 238000002474 experimental method Methods 0.000 description 12
- 238000002560 therapeutic procedure Methods 0.000 description 12
- 241000712461 unidentified influenza virus Species 0.000 description 12
- 208000002606 Paramyxoviridae Infections Diseases 0.000 description 11
- 238000006731 degradation reaction Methods 0.000 description 11
- 230000001036 exonucleolytic effect Effects 0.000 description 11
- 239000002718 pyrimidine nucleoside Substances 0.000 description 11
- 125000001424 substituent group Chemical group 0.000 description 11
- 208000014697 Acute lymphocytic leukaemia Diseases 0.000 description 10
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 10
- 208000006664 Precursor Cell Lymphoblastic Leukemia-Lymphoma Diseases 0.000 description 10
- 108020000999 Viral RNA Proteins 0.000 description 10
- 150000001412 amines Chemical class 0.000 description 10
- 239000003443 antiviral agent Substances 0.000 description 10
- 238000003556 assay Methods 0.000 description 10
- 230000000295 complement effect Effects 0.000 description 10
- 210000003128 head Anatomy 0.000 description 10
- 210000003739 neck Anatomy 0.000 description 10
- 230000006103 sulfonylation Effects 0.000 description 10
- 238000005694 sulfonylation reaction Methods 0.000 description 10
- 210000003932 urinary bladder Anatomy 0.000 description 10
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 9
- 101710154606 Hemagglutinin Proteins 0.000 description 9
- 108010050904 Interferons Proteins 0.000 description 9
- 102000014150 Interferons Human genes 0.000 description 9
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 9
- 101710144111 Non-structural protein 3 Proteins 0.000 description 9
- 101710093908 Outer capsid protein VP4 Proteins 0.000 description 9
- 101710135467 Outer capsid protein sigma-1 Proteins 0.000 description 9
- 101710176177 Protein A56 Proteins 0.000 description 9
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 9
- 229910002092 carbon dioxide Inorganic materials 0.000 description 9
- OFEZSBMBBKLLBJ-BAJZRUMYSA-N cordycepin Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)C[C@H]1O OFEZSBMBBKLLBJ-BAJZRUMYSA-N 0.000 description 9
- 239000000185 hemagglutinin Substances 0.000 description 9
- 229940079322 interferon Drugs 0.000 description 9
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 9
- 230000003647 oxidation Effects 0.000 description 9
- 238000007254 oxidation reaction Methods 0.000 description 9
- 239000008194 pharmaceutical composition Substances 0.000 description 9
- 230000002829 reductive effect Effects 0.000 description 9
- 230000000241 respiratory effect Effects 0.000 description 9
- 239000000758 substrate Substances 0.000 description 9
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 9
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 8
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 8
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- 208000032791 BCR-ABL1 positive chronic myelogenous leukemia Diseases 0.000 description 8
- 208000010833 Chronic myeloid leukaemia Diseases 0.000 description 8
- 108020004414 DNA Proteins 0.000 description 8
- 208000004576 Flaviviridae Infections Diseases 0.000 description 8
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 8
- 208000007766 Kaposi sarcoma Diseases 0.000 description 8
- 208000034578 Multiple myelomas Diseases 0.000 description 8
- 208000033761 Myelogenous Chronic BCR-ABL Positive Leukemia Diseases 0.000 description 8
- 206010029260 Neuroblastoma Diseases 0.000 description 8
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 8
- 206010035226 Plasma cell myeloma Diseases 0.000 description 8
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 8
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 8
- 238000006640 acetylation reaction Methods 0.000 description 8
- RJURFGZVJUQBHK-UHFFFAOYSA-N actinomycin D Natural products CC1OC(=O)C(C(C)C)N(C)C(=O)CN(C)C(=O)C2CCCN2C(=O)C(C(C)C)NC(=O)C1NC(=O)C1=C(N)C(=O)C(C)=C2OC(C(C)=CC=C3C(=O)NC4C(=O)NC(C(N5CCCC5C(=O)N(C)CC(=O)N(C)C(C(C)C)C(=O)OC4C)=O)C(C)C)=C3N=C21 RJURFGZVJUQBHK-UHFFFAOYSA-N 0.000 description 8
- OFEZSBMBBKLLBJ-UHFFFAOYSA-N cordycepine Natural products C1=NC=2C(N)=NC=NC=2N1C1OC(CO)CC1O OFEZSBMBBKLLBJ-UHFFFAOYSA-N 0.000 description 8
- 239000000975 dye Substances 0.000 description 8
- 239000000706 filtrate Substances 0.000 description 8
- FFUAGWLWBBFQJT-UHFFFAOYSA-N hexamethyldisilazane Chemical compound C[Si](C)(C)N[Si](C)(C)C FFUAGWLWBBFQJT-UHFFFAOYSA-N 0.000 description 8
- 239000000543 intermediate Substances 0.000 description 8
- 239000010410 layer Substances 0.000 description 8
- 201000001441 melanoma Diseases 0.000 description 8
- 230000035772 mutation Effects 0.000 description 8
- KWYUFKZDYYNOTN-UHFFFAOYSA-M potassium hydroxide Inorganic materials [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 8
- 238000011160 research Methods 0.000 description 8
- 208000000649 small cell carcinoma Diseases 0.000 description 8
- 239000011734 sodium Substances 0.000 description 8
- 235000009518 sodium iodide Nutrition 0.000 description 8
- 210000002784 stomach Anatomy 0.000 description 8
- 239000000725 suspension Substances 0.000 description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 8
- 229940113082 thymine Drugs 0.000 description 8
- WYWHKKSPHMUBEB-UHFFFAOYSA-N tioguanine Chemical compound N1C(N)=NC(=S)C2=C1N=CN2 WYWHKKSPHMUBEB-UHFFFAOYSA-N 0.000 description 8
- 241000710831 Flavivirus Species 0.000 description 7
- 241000712431 Influenza A virus Species 0.000 description 7
- 108060004795 Methyltransferase Proteins 0.000 description 7
- 206010061603 Respiratory syncytial virus infection Diseases 0.000 description 7
- 108091034135 Vault RNA Proteins 0.000 description 7
- 230000021736 acetylation Effects 0.000 description 7
- 150000001408 amides Chemical class 0.000 description 7
- 230000000692 anti-sense effect Effects 0.000 description 7
- CBHOOMGKXCMKIR-UHFFFAOYSA-N azane;methanol Chemical class N.OC CBHOOMGKXCMKIR-UHFFFAOYSA-N 0.000 description 7
- 239000000969 carrier Substances 0.000 description 7
- ODKNJVUHOIMIIZ-RRKCRQDMSA-N floxuridine Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(F)=C1 ODKNJVUHOIMIIZ-RRKCRQDMSA-N 0.000 description 7
- 238000009472 formulation Methods 0.000 description 7
- 239000012442 inert solvent Substances 0.000 description 7
- 230000003211 malignant effect Effects 0.000 description 7
- 108020004999 messenger RNA Proteins 0.000 description 7
- MRWXACSTFXYYMV-FDDDBJFASA-N nebularine Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C2=NC=NC=C2N=C1 MRWXACSTFXYYMV-FDDDBJFASA-N 0.000 description 7
- PGSADBUBUOPOJS-UHFFFAOYSA-N neutral red Chemical group Cl.C1=C(C)C(N)=CC2=NC3=CC(N(C)C)=CC=C3N=C21 PGSADBUBUOPOJS-UHFFFAOYSA-N 0.000 description 7
- 230000002035 prolonged effect Effects 0.000 description 7
- 210000002307 prostate Anatomy 0.000 description 7
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 7
- 238000010992 reflux Methods 0.000 description 7
- 239000002342 ribonucleoside Substances 0.000 description 7
- 238000012216 screening Methods 0.000 description 7
- 239000012279 sodium borohydride Substances 0.000 description 7
- 229910000033 sodium borohydride Inorganic materials 0.000 description 7
- 238000010561 standard procedure Methods 0.000 description 7
- FDKXTQMXEQVLRF-ZHACJKMWSA-N (E)-dacarbazine Chemical compound CN(C)\N=N\c1[nH]cnc1C(N)=O FDKXTQMXEQVLRF-ZHACJKMWSA-N 0.000 description 6
- QOXJRLADYHZRGC-SHYZEUOFSA-N 1-[(2r,3r,5s)-3-hydroxy-5-(hydroxymethyl)oxolan-2-yl]pyrimidine-2,4-dione Chemical class O1[C@H](CO)C[C@@H](O)[C@@H]1N1C(=O)NC(=O)C=C1 QOXJRLADYHZRGC-SHYZEUOFSA-N 0.000 description 6
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 6
- 229930024421 Adenine Natural products 0.000 description 6
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- 208000003174 Brain Neoplasms Diseases 0.000 description 6
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 6
- 102000004190 Enzymes Human genes 0.000 description 6
- 108090000790 Enzymes Proteins 0.000 description 6
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 6
- 208000005176 Hepatitis C Diseases 0.000 description 6
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 6
- 208000031422 Lymphocytic Chronic B-Cell Leukemia Diseases 0.000 description 6
- NWIBSHFKIJFRCO-WUDYKRTCSA-N Mytomycin Chemical compound C1N2C(C(C(C)=C(N)C3=O)=O)=C3[C@@H](COC(N)=O)[C@@]2(OC)[C@@H]2[C@H]1N2 NWIBSHFKIJFRCO-WUDYKRTCSA-N 0.000 description 6
- 108091092724 Noncoding DNA Proteins 0.000 description 6
- 241000710778 Pestivirus Species 0.000 description 6
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 6
- 101800001554 RNA-directed RNA polymerase Proteins 0.000 description 6
- 206010039491 Sarcoma Diseases 0.000 description 6
- 208000008383 Wilms tumor Diseases 0.000 description 6
- 230000009471 action Effects 0.000 description 6
- 229960000643 adenine Drugs 0.000 description 6
- 230000001028 anti-proliverative effect Effects 0.000 description 6
- 230000000890 antigenic effect Effects 0.000 description 6
- 239000012267 brine Substances 0.000 description 6
- 239000001569 carbon dioxide Substances 0.000 description 6
- 210000003679 cervix uteri Anatomy 0.000 description 6
- 210000001072 colon Anatomy 0.000 description 6
- 208000035250 cutaneous malignant susceptibility to 1 melanoma Diseases 0.000 description 6
- 231100000135 cytotoxicity Toxicity 0.000 description 6
- 230000003013 cytotoxicity Effects 0.000 description 6
- 230000001419 dependent effect Effects 0.000 description 6
- 238000001514 detection method Methods 0.000 description 6
- 229940088598 enzyme Drugs 0.000 description 6
- 229960003971 influenza vaccine Drugs 0.000 description 6
- 238000001990 intravenous administration Methods 0.000 description 6
- GLVAUDGFNGKCSF-UHFFFAOYSA-N mercaptopurine Chemical compound S=C1NC=NC2=C1NC=N2 GLVAUDGFNGKCSF-UHFFFAOYSA-N 0.000 description 6
- 201000005962 mycosis fungoides Diseases 0.000 description 6
- UEZVMMHDMIWARA-UHFFFAOYSA-M phosphonate Chemical compound [O-]P(=O)=O UEZVMMHDMIWARA-UHFFFAOYSA-M 0.000 description 6
- 230000003389 potentiating effect Effects 0.000 description 6
- 125000006239 protecting group Chemical group 0.000 description 6
- 238000000746 purification Methods 0.000 description 6
- 229920006395 saturated elastomer Polymers 0.000 description 6
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 6
- 239000006188 syrup Substances 0.000 description 6
- 235000020357 syrup Nutrition 0.000 description 6
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 description 6
- 238000005866 tritylation reaction Methods 0.000 description 6
- 229910052727 yttrium Inorganic materials 0.000 description 6
- OZAIFHULBGXAKX-UHFFFAOYSA-N 2-(2-cyanopropan-2-yldiazenyl)-2-methylpropanenitrile Chemical compound N#CC(C)(C)N=NC(C)(C)C#N OZAIFHULBGXAKX-UHFFFAOYSA-N 0.000 description 5
- GFFGJBXGBJISGV-UHFFFAOYSA-N Adenine Chemical compound NC1=NC=NC2=C1N=CN2 GFFGJBXGBJISGV-UHFFFAOYSA-N 0.000 description 5
- 241000283690 Bos taurus Species 0.000 description 5
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 5
- KQLDDLUWUFBQHP-UHFFFAOYSA-N Cordycepin Natural products C1=NC=2C(N)=NC=NC=2N1C1OCC(CO)C1O KQLDDLUWUFBQHP-UHFFFAOYSA-N 0.000 description 5
- 102000003886 Glycoproteins Human genes 0.000 description 5
- 108090000288 Glycoproteins Proteins 0.000 description 5
- 108700026244 Open Reading Frames Proteins 0.000 description 5
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 5
- 229910021627 Tin(IV) chloride Inorganic materials 0.000 description 5
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Natural products NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 5
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 5
- 150000007513 acids Chemical class 0.000 description 5
- 230000001154 acute effect Effects 0.000 description 5
- 150000001336 alkenes Chemical class 0.000 description 5
- 125000003282 alkyl amino group Chemical group 0.000 description 5
- 229940024606 amino acid Drugs 0.000 description 5
- 125000001769 aryl amino group Chemical group 0.000 description 5
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 5
- 244000309464 bull Species 0.000 description 5
- 230000001413 cellular effect Effects 0.000 description 5
- 208000019425 cirrhosis of liver Diseases 0.000 description 5
- STQGQHZAVUOBTE-VGBVRHCVSA-N daunorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(C)=O)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 STQGQHZAVUOBTE-VGBVRHCVSA-N 0.000 description 5
- 150000002148 esters Chemical class 0.000 description 5
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 5
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 5
- 238000007327 hydrogenolysis reaction Methods 0.000 description 5
- 230000007062 hydrolysis Effects 0.000 description 5
- 238000006460 hydrolysis reaction Methods 0.000 description 5
- 230000001965 increasing effect Effects 0.000 description 5
- 238000011534 incubation Methods 0.000 description 5
- 238000013101 initial test Methods 0.000 description 5
- 239000002054 inoculum Substances 0.000 description 5
- 208000032839 leukemia Diseases 0.000 description 5
- 239000000463 material Substances 0.000 description 5
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 5
- 229930014626 natural product Natural products 0.000 description 5
- 150000002924 oxiranes Chemical class 0.000 description 5
- 239000013641 positive control Substances 0.000 description 5
- 230000035755 proliferation Effects 0.000 description 5
- 238000011002 quantification Methods 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- HPGGPRDJHPYFRM-UHFFFAOYSA-J tin(iv) chloride Chemical compound Cl[Sn](Cl)(Cl)Cl HPGGPRDJHPYFRM-UHFFFAOYSA-J 0.000 description 5
- 230000001988 toxicity Effects 0.000 description 5
- 231100000419 toxicity Toxicity 0.000 description 5
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 5
- GVJHHUAWPYXKBD-UHFFFAOYSA-N (±)-α-Tocopherol Chemical compound OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 description 4
- YJQYHFMKGAVKDP-UHFFFAOYSA-N 3-butanoyl-1,8-dihydroxy-2-methylphenanthrene-9,10-dione Chemical compound C12=CC=CC(O)=C2C(=O)C(=O)C2=C1C=C(C(=O)CCC)C(C)=C2O YJQYHFMKGAVKDP-UHFFFAOYSA-N 0.000 description 4
- FVLVBPDQNARYJU-XAHDHGMMSA-N C[C@H]1CCC(CC1)NC(=O)N(CCCl)N=O Chemical compound C[C@H]1CCC(CC1)NC(=O)N(CCCl)N=O FVLVBPDQNARYJU-XAHDHGMMSA-N 0.000 description 4
- DLGOEMSEDOSKAD-UHFFFAOYSA-N Carmustine Chemical compound ClCCNC(=O)N(N=O)CCCl DLGOEMSEDOSKAD-UHFFFAOYSA-N 0.000 description 4
- JWBOIMRXGHLCPP-UHFFFAOYSA-N Chloditan Chemical compound C=1C=CC=C(Cl)C=1C(C(Cl)Cl)C1=CC=C(Cl)C=C1 JWBOIMRXGHLCPP-UHFFFAOYSA-N 0.000 description 4
- 208000006332 Choriocarcinoma Diseases 0.000 description 4
- UHDGCWIWMRVCDJ-CCXZUQQUSA-N Cytarabine Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@@H](O)[C@H](O)[C@@H](CO)O1 UHDGCWIWMRVCDJ-CCXZUQQUSA-N 0.000 description 4
- 108010092160 Dactinomycin Proteins 0.000 description 4
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 description 4
- KRHYYFGTRYWZRS-UHFFFAOYSA-M Fluoride anion Chemical compound [F-] KRHYYFGTRYWZRS-UHFFFAOYSA-M 0.000 description 4
- 241000711557 Hepacivirus Species 0.000 description 4
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 4
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 description 4
- GQYIWUVLTXOXAJ-UHFFFAOYSA-N Lomustine Chemical compound ClCCN(N=O)C(=O)NC1CCCCC1 GQYIWUVLTXOXAJ-UHFFFAOYSA-N 0.000 description 4
- 241000124008 Mammalia Species 0.000 description 4
- 238000005481 NMR spectroscopy Methods 0.000 description 4
- 101800001014 Non-structural protein 5A Proteins 0.000 description 4
- 208000009620 Orthomyxoviridae Infections Diseases 0.000 description 4
- 229910019142 PO4 Inorganic materials 0.000 description 4
- ZRWPUFFVAOMMNM-UHFFFAOYSA-N Patulin Chemical compound OC1OCC=C2OC(=O)C=C12 ZRWPUFFVAOMMNM-UHFFFAOYSA-N 0.000 description 4
- ABLZXFCXXLZCGV-UHFFFAOYSA-N Phosphorous acid Chemical compound OP(O)=O ABLZXFCXXLZCGV-UHFFFAOYSA-N 0.000 description 4
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 4
- 241000144282 Sigmodon Species 0.000 description 4
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 4
- NKANXQFJJICGDU-QPLCGJKRSA-N Tamoxifen Chemical compound C=1C=CC=CC=1C(/CC)=C(C=1C=CC(OCCN(C)C)=CC=1)/C1=CC=CC=C1 NKANXQFJJICGDU-QPLCGJKRSA-N 0.000 description 4
- JXLYSJRDGCGARV-WWYNWVTFSA-N Vinblastine Natural products O=C(O[C@H]1[C@](O)(C(=O)OC)[C@@H]2N(C)c3c(cc(c(OC)c3)[C@]3(C(=O)OC)c4[nH]c5c(c4CCN4C[C@](O)(CC)C[C@H](C3)C4)cccc5)[C@@]32[C@H]2[C@@]1(CC)C=CCN2CC3)C JXLYSJRDGCGARV-WWYNWVTFSA-N 0.000 description 4
- 238000010306 acid treatment Methods 0.000 description 4
- RJURFGZVJUQBHK-IIXSONLDSA-N actinomycin D Chemical compound C[C@H]1OC(=O)[C@H](C(C)C)N(C)C(=O)CN(C)C(=O)[C@@H]2CCCN2C(=O)[C@@H](C(C)C)NC(=O)[C@H]1NC(=O)C1=C(N)C(=O)C(C)=C2OC(C(C)=CC=C3C(=O)N[C@@H]4C(=O)N[C@@H](C(N5CCC[C@H]5C(=O)N(C)CC(=O)N(C)[C@@H](C(C)C)C(=O)O[C@@H]4C)=O)C(C)C)=C3N=C21 RJURFGZVJUQBHK-IIXSONLDSA-N 0.000 description 4
- 229910052783 alkali metal Inorganic materials 0.000 description 4
- 125000003545 alkoxy group Chemical group 0.000 description 4
- DKNWSYNQZKUICI-UHFFFAOYSA-N amantadine Chemical compound C1C(C2)CC3CC2CC1(N)C3 DKNWSYNQZKUICI-UHFFFAOYSA-N 0.000 description 4
- 229960003805 amantadine Drugs 0.000 description 4
- BFNBIHQBYMNNAN-UHFFFAOYSA-N ammonium sulfate Chemical compound N.N.OS(O)(=O)=O BFNBIHQBYMNNAN-UHFFFAOYSA-N 0.000 description 4
- 229910052921 ammonium sulfate Inorganic materials 0.000 description 4
- 235000011130 ammonium sulphate Nutrition 0.000 description 4
- 238000002832 anti-viral assay Methods 0.000 description 4
- 229940121357 antivirals Drugs 0.000 description 4
- 125000004104 aryloxy group Chemical group 0.000 description 4
- 239000003054 catalyst Substances 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- 238000002512 chemotherapy Methods 0.000 description 4
- 230000001684 chronic effect Effects 0.000 description 4
- MYSWGUAQZAJSOK-UHFFFAOYSA-N ciprofloxacin Chemical compound C12=CC(N3CCNCC3)=C(F)C=C2C(=O)C(C(=O)O)=CN1C1CC1 MYSWGUAQZAJSOK-UHFFFAOYSA-N 0.000 description 4
- 229960000640 dactinomycin Drugs 0.000 description 4
- 239000002552 dosage form Substances 0.000 description 4
- 241001493065 dsRNA viruses Species 0.000 description 4
- 210000004696 endometrium Anatomy 0.000 description 4
- 238000001704 evaporation Methods 0.000 description 4
- 230000008020 evaporation Effects 0.000 description 4
- 239000007850 fluorescent dye Substances 0.000 description 4
- 239000011737 fluorine Substances 0.000 description 4
- 125000000524 functional group Chemical group 0.000 description 4
- UYTPUPDQBNUYGX-UHFFFAOYSA-N guanine Chemical compound O=C1NC(N)=NC2=C1N=CN2 UYTPUPDQBNUYGX-UHFFFAOYSA-N 0.000 description 4
- 201000009277 hairy cell leukemia Diseases 0.000 description 4
- 150000004820 halides Chemical class 0.000 description 4
- 229940088597 hormone Drugs 0.000 description 4
- 239000005556 hormone Substances 0.000 description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 4
- WQYVRQLZKVEZGA-UHFFFAOYSA-N hypochlorite Inorganic materials Cl[O-] WQYVRQLZKVEZGA-UHFFFAOYSA-N 0.000 description 4
- 238000001727 in vivo Methods 0.000 description 4
- 210000003734 kidney Anatomy 0.000 description 4
- 239000012280 lithium aluminium hydride Substances 0.000 description 4
- AMXOYNBUYSYVKV-UHFFFAOYSA-M lithium bromide Chemical compound [Li+].[Br-] AMXOYNBUYSYVKV-UHFFFAOYSA-M 0.000 description 4
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 4
- SGDBTWWWUNNDEQ-LBPRGKRZSA-N melphalan Chemical compound OC(=O)[C@@H](N)CC1=CC=C(N(CCCl)CCCl)C=C1 SGDBTWWWUNNDEQ-LBPRGKRZSA-N 0.000 description 4
- 229960001428 mercaptopurine Drugs 0.000 description 4
- 238000003328 mesylation reaction Methods 0.000 description 4
- 229960000485 methotrexate Drugs 0.000 description 4
- CFCUWKMKBJTWLW-BKHRDMLASA-N mithramycin Chemical compound O([C@@H]1C[C@@H](O[C@H](C)[C@H]1O)OC=1C=C2C=C3C[C@H]([C@@H](C(=O)C3=C(O)C2=C(O)C=1C)O[C@@H]1O[C@H](C)[C@@H](O)[C@H](O[C@@H]2O[C@H](C)[C@H](O)[C@H](O[C@@H]3O[C@H](C)[C@@H](O)[C@@](C)(O)C3)C2)C1)[C@H](OC)C(=O)[C@@H](O)[C@@H](C)O)[C@H]1C[C@@H](O)[C@H](O)[C@@H](C)O1 CFCUWKMKBJTWLW-BKHRDMLASA-N 0.000 description 4
- 229960004857 mitomycin Drugs 0.000 description 4
- 238000012544 monitoring process Methods 0.000 description 4
- HDZGCSFEDULWCS-UHFFFAOYSA-N monomethylhydrazine Chemical class CNN HDZGCSFEDULWCS-UHFFFAOYSA-N 0.000 description 4
- 239000013642 negative control Substances 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- 108020004707 nucleic acids Proteins 0.000 description 4
- 102000039446 nucleic acids Human genes 0.000 description 4
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 description 4
- 229940046166 oligodeoxynucleotide Drugs 0.000 description 4
- 239000006186 oral dosage form Substances 0.000 description 4
- 201000008968 osteosarcoma Diseases 0.000 description 4
- 210000000496 pancreas Anatomy 0.000 description 4
- 239000010452 phosphate Substances 0.000 description 4
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 4
- 229960003171 plicamycin Drugs 0.000 description 4
- 239000002244 precipitate Substances 0.000 description 4
- CPTBDICYNRMXFX-UHFFFAOYSA-N procarbazine Chemical compound CNNCC1=CC=C(C(=O)NC(C)C)C=C1 CPTBDICYNRMXFX-UHFFFAOYSA-N 0.000 description 4
- 150000003254 radicals Chemical class 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- 208000030925 respiratory syncytial virus infectious disease Diseases 0.000 description 4
- 201000009410 rhabdomyosarcoma Diseases 0.000 description 4
- 238000007127 saponification reaction Methods 0.000 description 4
- 239000011669 selenium Substances 0.000 description 4
- 229960003440 semustine Drugs 0.000 description 4
- 238000010898 silica gel chromatography Methods 0.000 description 4
- 229910052708 sodium Inorganic materials 0.000 description 4
- 239000001632 sodium acetate Substances 0.000 description 4
- 235000017281 sodium acetate Nutrition 0.000 description 4
- 229910000104 sodium hydride Inorganic materials 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 229960001052 streptozocin Drugs 0.000 description 4
- ZSJLQEPLLKMAKR-GKHCUFPYSA-N streptozocin Chemical compound O=NN(C)C(=O)N[C@H]1[C@@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O ZSJLQEPLLKMAKR-GKHCUFPYSA-N 0.000 description 4
- 239000006228 supernatant Substances 0.000 description 4
- 239000000829 suppository Substances 0.000 description 4
- 125000000037 tert-butyldiphenylsilyl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1[Si]([H])([*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 4
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 4
- 150000003548 thiazolidines Chemical class 0.000 description 4
- CWERGRDVMFNCDR-UHFFFAOYSA-N thioglycolic acid Chemical compound OC(=O)CS CWERGRDVMFNCDR-UHFFFAOYSA-N 0.000 description 4
- 210000001685 thyroid gland Anatomy 0.000 description 4
- 229960003087 tioguanine Drugs 0.000 description 4
- 238000013519 translation Methods 0.000 description 4
- JXLYSJRDGCGARV-XQKSVPLYSA-N vincaleukoblastine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 JXLYSJRDGCGARV-XQKSVPLYSA-N 0.000 description 4
- 230000029812 viral genome replication Effects 0.000 description 4
- UGRNVLGKAGREKS-GCXDCGAKSA-N (1r,2s,3r,5r)-3-(6-aminopurin-9-yl)-5-(hydroxymethyl)cyclopentane-1,2-diol Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1C[C@H](CO)[C@@H](O)[C@H]1O UGRNVLGKAGREKS-GCXDCGAKSA-N 0.000 description 3
- RKSLVDIXBGWPIS-UAKXSSHOSA-N 1-[(2r,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-5-iodopyrimidine-2,4-dione Chemical class O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(I)=C1 RKSLVDIXBGWPIS-UAKXSSHOSA-N 0.000 description 3
- GIVZQHLRPFAYJX-LKEWCRSYSA-N 1-[(2r,3r,5s)-3-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-5-(hydroxymethyl)pyrimidine-2,4-dione Chemical compound O1[C@H](CO)C[C@@H](O)[C@@H]1N1C(=O)NC(=O)C(CO)=C1 GIVZQHLRPFAYJX-LKEWCRSYSA-N 0.000 description 3
- OROIAVZITJBGSM-OBXARNEKSA-N 3'-deoxyguanosine Chemical compound C1=2NC(N)=NC(=O)C=2N=CN1[C@@H]1O[C@H](CO)C[C@H]1O OROIAVZITJBGSM-OBXARNEKSA-N 0.000 description 3
- HAVVCBYMVOGGRT-UHFFFAOYSA-N 3-methoxyprop-2-enoyl isocyanate Chemical compound COC=CC(=O)N=C=O HAVVCBYMVOGGRT-UHFFFAOYSA-N 0.000 description 3
- RBUINSFJQSHMRE-CVTKMRTPSA-N 5-fluoro-1-[(2r,3r,5s)-3-hydroxy-5-(hydroxymethyl)oxolan-2-yl]pyrimidine-2,4-dione Chemical compound O1[C@H](CO)C[C@@H](O)[C@@H]1N1C(=O)NC(=O)C(F)=C1 RBUINSFJQSHMRE-CVTKMRTPSA-N 0.000 description 3
- ZKBQDFAWXLTYKS-UHFFFAOYSA-N 6-Chloro-1H-purine Chemical compound ClC1=NC=NC2=C1NC=N2 ZKBQDFAWXLTYKS-UHFFFAOYSA-N 0.000 description 3
- KHAHRMWUNUSUBA-CVTKMRTPSA-N 6-amino-3-[(2r,3r,5s)-3-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-2-oxopyrimidine-4-carboxylic acid Chemical compound O=C1N=C(N)C=C(C(O)=O)N1[C@H]1[C@H](O)C[C@@H](CO)O1 KHAHRMWUNUSUBA-CVTKMRTPSA-N 0.000 description 3
- STQGQHZAVUOBTE-UHFFFAOYSA-N 7-Cyan-hept-2t-en-4,6-diinsaeure Natural products C1=2C(O)=C3C(=O)C=4C(OC)=CC=CC=4C(=O)C3=C(O)C=2CC(O)(C(C)=O)CC1OC1CC(N)C(O)C(C)O1 STQGQHZAVUOBTE-UHFFFAOYSA-N 0.000 description 3
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 3
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 3
- 208000023275 Autoimmune disease Diseases 0.000 description 3
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 3
- 241000710777 Classical swine fever virus Species 0.000 description 3
- 241000725619 Dengue virus Species 0.000 description 3
- 206010059866 Drug resistance Diseases 0.000 description 3
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 3
- 102100038132 Endogenous retrovirus group K member 6 Pro protein Human genes 0.000 description 3
- 108010037362 Extracellular Matrix Proteins Proteins 0.000 description 3
- 102000010834 Extracellular Matrix Proteins Human genes 0.000 description 3
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- NYHBQMYGNKIUIF-UUOKFMHZSA-N Guanosine Chemical compound C1=NC=2C(=O)NC(N)=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O NYHBQMYGNKIUIF-UUOKFMHZSA-N 0.000 description 3
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 3
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 description 3
- 241000710843 Japanese encephalitis virus group Species 0.000 description 3
- IOVCWXUNBOPUCH-UHFFFAOYSA-N Nitrous acid Chemical compound ON=O IOVCWXUNBOPUCH-UHFFFAOYSA-N 0.000 description 3
- 101800001020 Non-structural protein 4A Proteins 0.000 description 3
- 108010076039 Polyproteins Proteins 0.000 description 3
- 201000004681 Psoriasis Diseases 0.000 description 3
- 108091034057 RNA (poly(A)) Proteins 0.000 description 3
- 101800001838 Serine protease/helicase NS3 Proteins 0.000 description 3
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 3
- 108020005202 Viral DNA Proteins 0.000 description 3
- 241000710772 Yellow fever virus Species 0.000 description 3
- TXWMDTGSEVKMJU-HOSYDEDBSA-N [(2s,4r,5r)-4-acetyloxy-5-(2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methyl acetate Chemical compound O1[C@H](COC(=O)C)C[C@@H](OC(C)=O)[C@@H]1N1C(=O)NC(=O)C=C1 TXWMDTGSEVKMJU-HOSYDEDBSA-N 0.000 description 3
- FXXACINHVKSMDR-UHFFFAOYSA-N acetyl bromide Chemical compound CC(Br)=O FXXACINHVKSMDR-UHFFFAOYSA-N 0.000 description 3
- 230000010933 acylation Effects 0.000 description 3
- 238000005917 acylation reaction Methods 0.000 description 3
- 125000004423 acyloxy group Chemical group 0.000 description 3
- 239000000654 additive Substances 0.000 description 3
- 150000001298 alcohols Chemical class 0.000 description 3
- 150000001340 alkali metals Chemical class 0.000 description 3
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 3
- 150000001342 alkaline earth metals Chemical class 0.000 description 3
- 150000001350 alkyl halides Chemical class 0.000 description 3
- 229940100198 alkylating agent Drugs 0.000 description 3
- 239000002168 alkylating agent Substances 0.000 description 3
- 125000003368 amide group Chemical group 0.000 description 3
- 229910021529 ammonia Inorganic materials 0.000 description 3
- 239000000908 ammonium hydroxide Substances 0.000 description 3
- 150000008064 anhydrides Chemical class 0.000 description 3
- 239000005557 antagonist Substances 0.000 description 3
- 239000003242 anti bacterial agent Substances 0.000 description 3
- 230000000340 anti-metabolite Effects 0.000 description 3
- 229940100197 antimetabolite Drugs 0.000 description 3
- 239000002256 antimetabolite Substances 0.000 description 3
- 239000002246 antineoplastic agent Substances 0.000 description 3
- 230000003190 augmentative effect Effects 0.000 description 3
- SIPUZPBQZHNSDW-UHFFFAOYSA-N bis(2-methylpropyl)aluminum Chemical compound CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 description 3
- 229910000019 calcium carbonate Inorganic materials 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 3
- 230000003197 catalytic effect Effects 0.000 description 3
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 3
- 238000004113 cell culture Methods 0.000 description 3
- 239000003638 chemical reducing agent Substances 0.000 description 3
- 238000013375 chromatographic separation Methods 0.000 description 3
- 238000002648 combination therapy Methods 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 125000004122 cyclic group Chemical group 0.000 description 3
- UHDGCWIWMRVCDJ-ZAKLUEHWSA-N cytidine Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O1 UHDGCWIWMRVCDJ-ZAKLUEHWSA-N 0.000 description 3
- 229960000975 daunorubicin Drugs 0.000 description 3
- 238000010511 deprotection reaction Methods 0.000 description 3
- 238000011161 development Methods 0.000 description 3
- 230000018109 developmental process Effects 0.000 description 3
- 125000004663 dialkyl amino group Chemical group 0.000 description 3
- 239000003085 diluting agent Substances 0.000 description 3
- 238000010790 dilution Methods 0.000 description 3
- 239000012895 dilution Substances 0.000 description 3
- 210000002744 extracellular matrix Anatomy 0.000 description 3
- 239000000284 extract Substances 0.000 description 3
- 230000003176 fibrotic effect Effects 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 239000012025 fluorinating agent Substances 0.000 description 3
- 239000006260 foam Substances 0.000 description 3
- 230000006870 function Effects 0.000 description 3
- 125000001188 haloalkyl group Chemical group 0.000 description 3
- 125000005843 halogen group Chemical group 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 150000002466 imines Chemical class 0.000 description 3
- 239000000367 immunologic factor Substances 0.000 description 3
- 238000009169 immunotherapy Methods 0.000 description 3
- 208000037799 influenza C Diseases 0.000 description 3
- 238000007918 intramuscular administration Methods 0.000 description 3
- 239000011630 iodine Substances 0.000 description 3
- 150000002632 lipids Chemical class 0.000 description 3
- 238000006140 methanolysis reaction Methods 0.000 description 3
- XUGWUUDOWNZAGW-UHFFFAOYSA-N neplanocin A Natural products C1=NC=2C(N)=NC=NC=2N1C1C=C(CO)C(O)C1O XUGWUUDOWNZAGW-UHFFFAOYSA-N 0.000 description 3
- LBQAJLBSGOBDQF-UHFFFAOYSA-N nitro azanylidynemethanesulfonate Chemical compound [O-][N+](=O)OS(=O)(=O)C#N LBQAJLBSGOBDQF-UHFFFAOYSA-N 0.000 description 3
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 3
- 150000002923 oximes Chemical class 0.000 description 3
- 230000000144 pharmacologic effect Effects 0.000 description 3
- 125000005328 phosphinyl group Chemical group [PH2](=O)* 0.000 description 3
- 125000005499 phosphonyl group Chemical group 0.000 description 3
- 229910000073 phosphorus hydride Inorganic materials 0.000 description 3
- LFGREXWGYUGZLY-UHFFFAOYSA-N phosphoryl Chemical group [P]=O LFGREXWGYUGZLY-UHFFFAOYSA-N 0.000 description 3
- 229910052700 potassium Inorganic materials 0.000 description 3
- 239000011591 potassium Substances 0.000 description 3
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 3
- 230000036515 potency Effects 0.000 description 3
- 230000002265 prevention Effects 0.000 description 3
- 238000012545 processing Methods 0.000 description 3
- 102000004169 proteins and genes Human genes 0.000 description 3
- 230000004044 response Effects 0.000 description 3
- 210000003491 skin Anatomy 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- 241000894007 species Species 0.000 description 3
- 230000000707 stereoselective effect Effects 0.000 description 3
- 230000035882 stress Effects 0.000 description 3
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 description 3
- 150000003457 sulfones Chemical class 0.000 description 3
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 3
- 208000011580 syndromic disease Diseases 0.000 description 3
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical group C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 description 3
- 230000001225 therapeutic effect Effects 0.000 description 3
- 238000004809 thin layer chromatography Methods 0.000 description 3
- 150000007970 thio esters Chemical class 0.000 description 3
- 150000003568 thioethers Chemical class 0.000 description 3
- 125000003396 thiol group Chemical group [H]S* 0.000 description 3
- 150000003573 thiols Chemical class 0.000 description 3
- 210000001519 tissue Anatomy 0.000 description 3
- 230000000699 topical effect Effects 0.000 description 3
- 238000013518 transcription Methods 0.000 description 3
- 230000035897 transcription Effects 0.000 description 3
- GRGCWBWNLSTIEN-UHFFFAOYSA-N trifluoromethanesulfonyl chloride Chemical compound FC(F)(F)S(Cl)(=O)=O GRGCWBWNLSTIEN-UHFFFAOYSA-N 0.000 description 3
- 230000017613 viral reproduction Effects 0.000 description 3
- 230000003442 weekly effect Effects 0.000 description 3
- QKHSJWMRKTZSRT-MVKOHCKWSA-N (2r,3r,5s)-5-(hydroxymethyl)-2-(6-methoxypurin-9-yl)oxolan-3-ol Chemical compound C1=NC=2C(OC)=NC=NC=2N1[C@@H]1O[C@H](CO)C[C@H]1O QKHSJWMRKTZSRT-MVKOHCKWSA-N 0.000 description 2
- ZZKNRXZVGOYGJT-VKHMYHEASA-N (2s)-2-[(2-phosphonoacetyl)amino]butanedioic acid Chemical compound OC(=O)C[C@@H](C(O)=O)NC(=O)CP(O)(O)=O ZZKNRXZVGOYGJT-VKHMYHEASA-N 0.000 description 2
- IVWWFWFVSWOTLP-YVZVNANGSA-N (3'as,4r,7'as)-2,2,2',2'-tetramethylspiro[1,3-dioxolane-4,6'-4,7a-dihydro-3ah-[1,3]dioxolo[4,5-c]pyran]-7'-one Chemical compound C([C@@H]1OC(O[C@@H]1C1=O)(C)C)O[C@]21COC(C)(C)O2 IVWWFWFVSWOTLP-YVZVNANGSA-N 0.000 description 2
- XFLOJOXQDZMCRP-YRZWDFBDSA-N (3r,5s)-5-(hydroxymethyl)-2-methoxyoxolan-3-ol Chemical compound COC1O[C@H](CO)C[C@H]1O XFLOJOXQDZMCRP-YRZWDFBDSA-N 0.000 description 2
- YYGNTYWPHWGJRM-UHFFFAOYSA-N (6E,10E,14E,18E)-2,6,10,15,19,23-hexamethyltetracosa-2,6,10,14,18,22-hexaene Chemical compound CC(C)=CCCC(C)=CCCC(C)=CCCC=C(C)CCC=C(C)CCC=C(C)C YYGNTYWPHWGJRM-UHFFFAOYSA-N 0.000 description 2
- FPVKHBSQESCIEP-UHFFFAOYSA-N (8S)-3-(2-deoxy-beta-D-erythro-pentofuranosyl)-3,6,7,8-tetrahydroimidazo[4,5-d][1,3]diazepin-8-ol Natural products C1C(O)C(CO)OC1N1C(NC=NCC2O)=C2N=C1 FPVKHBSQESCIEP-UHFFFAOYSA-N 0.000 description 2
- 102000040650 (ribonucleotides)n+m Human genes 0.000 description 2
- SJCDBQHCQSIZHN-UHFFFAOYSA-N 1,2-dihydrotriazole-3-carboxamide Chemical compound NC(=O)N1NNC=C1 SJCDBQHCQSIZHN-UHFFFAOYSA-N 0.000 description 2
- UBCHPRBFMUDMNC-UHFFFAOYSA-N 1-(1-adamantyl)ethanamine Chemical compound C1C(C2)CC3CC2CC1(C(N)C)C3 UBCHPRBFMUDMNC-UHFFFAOYSA-N 0.000 description 2
- QSHRORQBJAVCRL-UAKXSSHOSA-N 1-[(2r,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-5-nitropyrimidine-2,4-dione Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C([N+]([O-])=O)=C1 QSHRORQBJAVCRL-UAKXSSHOSA-N 0.000 description 2
- ZPBRIWRUKVZCRW-XVFCMESISA-N 1-[(2r,3s,4s,5r)-3-hydroxy-5-(hydroxymethyl)-4-iodooxolan-2-yl]pyrimidine-2,4-dione Chemical compound O[C@@H]1[C@H](I)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C=C1 ZPBRIWRUKVZCRW-XVFCMESISA-N 0.000 description 2
- 102100025573 1-alkyl-2-acetylglycerophosphocholine esterase Human genes 0.000 description 2
- UHDGCWIWMRVCDJ-UHFFFAOYSA-N 1-beta-D-Xylofuranosyl-NH-Cytosine Natural products O=C1N=C(N)C=CN1C1C(O)C(O)C(CO)O1 UHDGCWIWMRVCDJ-UHFFFAOYSA-N 0.000 description 2
- GVEZIHKRYBHEFX-MNOVXSKESA-N 13C-Cerulenin Natural products CC=CCC=CCCC(=O)[C@H]1O[C@@H]1C(N)=O GVEZIHKRYBHEFX-MNOVXSKESA-N 0.000 description 2
- RQFCJASXJCIDSX-UHFFFAOYSA-N 14C-Guanosin-5'-monophosphat Natural products C1=2NC(N)=NC(=O)C=2N=CN1C1OC(COP(O)(O)=O)C(O)C1O RQFCJASXJCIDSX-UHFFFAOYSA-N 0.000 description 2
- BFPYWIDHMRZLRN-UHFFFAOYSA-N 17alpha-ethynyl estradiol Natural products OC1=CC=C2C3CCC(C)(C(CC4)(O)C#C)C4C3CCC2=C1 BFPYWIDHMRZLRN-UHFFFAOYSA-N 0.000 description 2
- JAPYIBBSTJFDAK-UHFFFAOYSA-N 2,4,6-tri(propan-2-yl)benzenesulfonyl chloride Chemical compound CC(C)C1=CC(C(C)C)=C(S(Cl)(=O)=O)C(C(C)C)=C1 JAPYIBBSTJFDAK-UHFFFAOYSA-N 0.000 description 2
- SWRNFRDSVOHRAM-UHFFFAOYSA-N 2,4,6-trihydroxy-3-nitro-n-(4-phenoxyphenyl)benzamide Chemical compound OC1=CC(O)=C([N+]([O-])=O)C(O)=C1C(=O)NC(C=C1)=CC=C1OC1=CC=CC=C1 SWRNFRDSVOHRAM-UHFFFAOYSA-N 0.000 description 2
- CEHJYEXLKQVWOT-UHFFFAOYSA-N 2,4,6-trihydroxy-3-nitrobenzamide Chemical class NC(=O)C1=C(O)C=C(O)C([N+]([O-])=O)=C1O CEHJYEXLKQVWOT-UHFFFAOYSA-N 0.000 description 2
- GOJUJUVQIVIZAV-UHFFFAOYSA-N 2-amino-4,6-dichloropyrimidine-5-carbaldehyde Chemical group NC1=NC(Cl)=C(C=O)C(Cl)=N1 GOJUJUVQIVIZAV-UHFFFAOYSA-N 0.000 description 2
- MWBWWFOAEOYUST-UHFFFAOYSA-N 2-aminopurine Chemical compound NC1=NC=C2N=CNC2=N1 MWBWWFOAEOYUST-UHFFFAOYSA-N 0.000 description 2
- CWNPOQFCIIFQDM-UHFFFAOYSA-N 3-nitrobenzyl alcohol Chemical compound OCC1=CC=CC([N+]([O-])=O)=C1 CWNPOQFCIIFQDM-UHFFFAOYSA-N 0.000 description 2
- MPWADGGTLJUMSO-LKEWCRSYSA-N 4-amino-1-[(2r,3r,5s)-3-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-6-methylpyrimidin-2-one Chemical compound CC1=CC(N)=NC(=O)N1[C@H]1[C@H](O)C[C@@H](CO)O1 MPWADGGTLJUMSO-LKEWCRSYSA-N 0.000 description 2
- NQMGIWOIYGQQCP-UHFFFAOYSA-N 4-amino-4-benzoyl-5-ethyl-1,3-dihydropyrimidin-2-one Chemical compound CCC1=CNC(=O)NC1(N)C(=O)C1=CC=CC=C1 NQMGIWOIYGQQCP-UHFFFAOYSA-N 0.000 description 2
- MMTNUUIFZSWOKI-UHFFFAOYSA-N 4-amino-4-benzoyl-5-methyl-1,3-dihydropyrimidin-2-one Chemical compound C(C1=CC=CC=C1)(=O)C1(NC(NC=C1C)=O)N MMTNUUIFZSWOKI-UHFFFAOYSA-N 0.000 description 2
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 2
- 101710169336 5'-deoxyadenosine deaminase Proteins 0.000 description 2
- AGFIRQJZCNVMCW-UAKXSSHOSA-N 5-bromouridine Chemical group O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(Br)=C1 AGFIRQJZCNVMCW-UAKXSSHOSA-N 0.000 description 2
- VEIPDPYFJUUBOQ-AIKLKQDHSA-N 5-fluoro-1-[(2r,3r,4s,5r)-4-hydroxy-5-(hydroxymethyl)-3-methyloxolan-2-yl]pyrimidine-2,4-dione Chemical compound C[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(F)=C1 VEIPDPYFJUUBOQ-AIKLKQDHSA-N 0.000 description 2
- ZNCNDMQEPOTIIV-CPDSJTNBSA-N 5-hydroxy-1-[(2r,3r,5s)-3-hydroxy-5-(hydroxymethyl)oxolan-2-yl]pyrimidine-2,4-dione Chemical compound O1[C@H](CO)C[C@@H](O)[C@@H]1N1C(=O)NC(=O)C(O)=C1 ZNCNDMQEPOTIIV-CPDSJTNBSA-N 0.000 description 2
- QXDXBKZJFLRLCM-UAKXSSHOSA-N 5-hydroxyuridine Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(O)=C1 QXDXBKZJFLRLCM-UAKXSSHOSA-N 0.000 description 2
- PNWOYKVCNDZOLS-UHFFFAOYSA-N 6-amino-5-chloro-1h-pyrimidin-2-one Chemical compound NC=1NC(=O)N=CC=1Cl PNWOYKVCNDZOLS-UHFFFAOYSA-N 0.000 description 2
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 2
- RPZDLTVHZJHPAW-BAJZRUMYSA-N 9-[(2r,3r,5s)-3-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-3h-purin-6-one Chemical compound O1[C@H](CO)C[C@@H](O)[C@@H]1N1C(NC=NC2=O)=C2N=C1 RPZDLTVHZJHPAW-BAJZRUMYSA-N 0.000 description 2
- GSDSWSVVBLHKDQ-UHFFFAOYSA-N 9-fluoro-3-methyl-10-(4-methylpiperazin-1-yl)-7-oxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxylic acid Chemical compound FC1=CC(C(C(C(O)=O)=C2)=O)=C3N2C(C)COC3=C1N1CCN(C)CC1 GSDSWSVVBLHKDQ-UHFFFAOYSA-N 0.000 description 2
- 208000030507 AIDS Diseases 0.000 description 2
- 206010000830 Acute leukaemia Diseases 0.000 description 2
- 102000055025 Adenosine deaminases Human genes 0.000 description 2
- 102400000068 Angiostatin Human genes 0.000 description 2
- 108010079709 Angiostatins Proteins 0.000 description 2
- 241000907515 Apoi virus Species 0.000 description 2
- 229930186232 Aristeromycin Natural products 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- 108010024976 Asparaginase Proteins 0.000 description 2
- 201000001320 Atherosclerosis Diseases 0.000 description 2
- IVRMZWNICZWHMI-UHFFFAOYSA-N Azide Chemical compound [N-]=[N+]=[N-] IVRMZWNICZWHMI-UHFFFAOYSA-N 0.000 description 2
- NOWKCMXCCJGMRR-UHFFFAOYSA-N Aziridine Chemical class C1CN1 NOWKCMXCCJGMRR-UHFFFAOYSA-N 0.000 description 2
- 208000010839 B-cell chronic lymphocytic leukemia Diseases 0.000 description 2
- DWRXFEITVBNRMK-UHFFFAOYSA-N Beta-D-1-Arabinofuranosylthymine Natural products O=C1NC(=O)C(C)=CN1C1C(O)C(O)C(CO)O1 DWRXFEITVBNRMK-UHFFFAOYSA-N 0.000 description 2
- 108010006654 Bleomycin Proteins 0.000 description 2
- 241001118702 Border disease virus Species 0.000 description 2
- 241000711895 Bovine orthopneumovirus Species 0.000 description 2
- COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 description 2
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- 108090000994 Catalytic RNA Proteins 0.000 description 2
- 102000053642 Catalytic RNA Human genes 0.000 description 2
- 241000282552 Chlorocebus aethiops Species 0.000 description 2
- 108091026890 Coding region Proteins 0.000 description 2
- 102100021906 Cyclin-O Human genes 0.000 description 2
- RGSFGYAAUTVSQA-UHFFFAOYSA-N Cyclopentane Chemical compound C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 description 2
- BZKFMUIJRXWWQK-UHFFFAOYSA-N Cyclopentenone Chemical compound O=C1CCC=C1 BZKFMUIJRXWWQK-UHFFFAOYSA-N 0.000 description 2
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 description 2
- UHDGCWIWMRVCDJ-PSQAKQOGSA-N Cytidine Natural products O=C1N=C(N)C=CN1[C@@H]1[C@@H](O)[C@@H](O)[C@H](CO)O1 UHDGCWIWMRVCDJ-PSQAKQOGSA-N 0.000 description 2
- CUOKHACJLGPRHD-BXXZVTAOSA-N D-ribono-1,4-lactone Chemical compound OC[C@H]1OC(=O)[C@H](O)[C@@H]1O CUOKHACJLGPRHD-BXXZVTAOSA-N 0.000 description 2
- 102000053602 DNA Human genes 0.000 description 2
- 108090000626 DNA-directed RNA polymerases Proteins 0.000 description 2
- 102000004163 DNA-directed RNA polymerases Human genes 0.000 description 2
- WEAHRLBPCANXCN-UHFFFAOYSA-N Daunomycin Natural products CCC1(O)CC(OC2CC(N)C(O)C(C)O2)c3cc4C(=O)c5c(OC)cccc5C(=O)c4c(O)c3C1 WEAHRLBPCANXCN-UHFFFAOYSA-N 0.000 description 2
- BXZVVICBKDXVGW-NKWVEPMBSA-N Didanosine Chemical compound O1[C@H](CO)CC[C@@H]1N1C(NC=NC2=O)=C2N=C1 BXZVVICBKDXVGW-NKWVEPMBSA-N 0.000 description 2
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 2
- GUUVPOWQJOLRAS-UHFFFAOYSA-N Diphenyl disulfide Chemical compound C=1C=CC=CC=1SSC1=CC=CC=C1 GUUVPOWQJOLRAS-UHFFFAOYSA-N 0.000 description 2
- 102400001047 Endostatin Human genes 0.000 description 2
- 108010079505 Endostatins Proteins 0.000 description 2
- 208000032027 Essential Thrombocythemia Diseases 0.000 description 2
- BFPYWIDHMRZLRN-SLHNCBLASA-N Ethinyl estradiol Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@](CC4)(O)C#C)[C@@H]4[C@@H]3CCC2=C1 BFPYWIDHMRZLRN-SLHNCBLASA-N 0.000 description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
- 229940124683 HCV polymerase inhibitor Drugs 0.000 description 2
- 206010019799 Hepatitis viral Diseases 0.000 description 2
- 241000545744 Hirudinea Species 0.000 description 2
- 101000897441 Homo sapiens Cyclin-O Proteins 0.000 description 2
- 101000600434 Homo sapiens Putative uncharacterized protein encoded by MIR7-3HG Proteins 0.000 description 2
- 241000713772 Human immunodeficiency virus 1 Species 0.000 description 2
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 2
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 description 2
- VSNHCAURESNICA-UHFFFAOYSA-N Hydroxyurea Chemical compound NC(=O)NO VSNHCAURESNICA-UHFFFAOYSA-N 0.000 description 2
- 241000713196 Influenza B virus Species 0.000 description 2
- 229940124873 Influenza virus vaccine Drugs 0.000 description 2
- 108010078049 Interferon alpha-2 Proteins 0.000 description 2
- 108010047761 Interferon-alpha Proteins 0.000 description 2
- 102000006992 Interferon-alpha Human genes 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- 108010000817 Leuprolide Proteins 0.000 description 2
- GSDSWSVVBLHKDQ-JTQLQIEISA-N Levofloxacin Chemical compound C([C@@H](N1C2=C(C(C(C(O)=O)=C1)=O)C=C1F)C)OC2=C1N1CCN(C)CC1 GSDSWSVVBLHKDQ-JTQLQIEISA-N 0.000 description 2
- 241000701076 Macacine alphaherpesvirus 1 Species 0.000 description 2
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- 108010090054 Membrane Glycoproteins Proteins 0.000 description 2
- 102000012750 Membrane Glycoproteins Human genes 0.000 description 2
- 206010027476 Metastases Diseases 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- BAPJBEWLBFYGME-UHFFFAOYSA-N Methyl acrylate Chemical compound COC(=O)C=C BAPJBEWLBFYGME-UHFFFAOYSA-N 0.000 description 2
- 238000006845 Michael addition reaction Methods 0.000 description 2
- 229930192392 Mitomycin Natural products 0.000 description 2
- 241000711941 Murine orthopneumovirus Species 0.000 description 2
- 241000699666 Mus <mouse, genus> Species 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- XCUAIINAJCDIPM-XVFCMESISA-N N(4)-hydroxycytidine Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=NO)C=C1 XCUAIINAJCDIPM-XVFCMESISA-N 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- 229910002651 NO3 Inorganic materials 0.000 description 2
- 239000007832 Na2SO4 Substances 0.000 description 2
- 102000005348 Neuraminidase Human genes 0.000 description 2
- 108010006232 Neuraminidase Proteins 0.000 description 2
- 101710163270 Nuclease Proteins 0.000 description 2
- 241000282579 Pan Species 0.000 description 2
- 241000228143 Penicillium Species 0.000 description 2
- 108091005804 Peptidases Proteins 0.000 description 2
- 241000711904 Pneumoviridae Species 0.000 description 2
- 241000288906 Primates Species 0.000 description 2
- 239000004365 Protease Substances 0.000 description 2
- 102100037401 Putative uncharacterized protein encoded by MIR7-3HG Human genes 0.000 description 2
- 238000011529 RT qPCR Methods 0.000 description 2
- 108010022999 Serine Proteases Proteins 0.000 description 2
- 102000012479 Serine Proteases Human genes 0.000 description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 2
- 241000187180 Streptomyces sp. Species 0.000 description 2
- 241000282898 Sus scrofa Species 0.000 description 2
- 206010042971 T-cell lymphoma Diseases 0.000 description 2
- 208000027585 T-cell non-Hodgkin lymphoma Diseases 0.000 description 2
- PDMMFKSKQVNJMI-BLQWBTBKSA-N Testosterone propionate Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](OC(=O)CC)[C@@]1(C)CC2 PDMMFKSKQVNJMI-BLQWBTBKSA-N 0.000 description 2
- BHEOSNUKNHRBNM-UHFFFAOYSA-N Tetramethylsqualene Natural products CC(=C)C(C)CCC(=C)C(C)CCC(C)=CCCC=C(C)CCC(C)C(=C)CCC(C)C(C)=C BHEOSNUKNHRBNM-UHFFFAOYSA-N 0.000 description 2
- FOCVUCIESVLUNU-UHFFFAOYSA-N Thiotepa Chemical compound C1CN1P(N1CC1)(=S)N1CC1 FOCVUCIESVLUNU-UHFFFAOYSA-N 0.000 description 2
- 241000711955 Turkey rhinotracheitis virus Species 0.000 description 2
- 229910052770 Uranium Inorganic materials 0.000 description 2
- 229940122803 Vinca alkaloid Drugs 0.000 description 2
- 229930003427 Vitamin E Natural products 0.000 description 2
- 208000033559 Waldenström macroglobulinemia Diseases 0.000 description 2
- OCXKLLNDHRILEL-QIIDTADFSA-N [(3r,5s)-2-acetyloxy-5-(methoxycarbonyloxymethyl)oxolan-3-yl] acetate Chemical compound COC(=O)OC[C@@H]1C[C@@H](OC(C)=O)C(OC(C)=O)O1 OCXKLLNDHRILEL-QIIDTADFSA-N 0.000 description 2
- 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 description 2
- 150000001266 acyl halides Chemical class 0.000 description 2
- OIRDTQYFTABQOQ-KQYNXXCUSA-N adenosine Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O OIRDTQYFTABQOQ-KQYNXXCUSA-N 0.000 description 2
- 210000004404 adrenal cortex Anatomy 0.000 description 2
- 230000001780 adrenocortical effect Effects 0.000 description 2
- 150000001299 aldehydes Chemical class 0.000 description 2
- 229940045714 alkyl sulfonate alkylating agent Drugs 0.000 description 2
- 150000008052 alkyl sulfonates Chemical class 0.000 description 2
- 230000029936 alkylation Effects 0.000 description 2
- 238000005804 alkylation reaction Methods 0.000 description 2
- 125000002947 alkylene group Chemical group 0.000 description 2
- 229960000473 altretamine Drugs 0.000 description 2
- ROBVIMPUHSLWNV-UHFFFAOYSA-N aminoglutethimide Chemical compound C=1C=C(N)C=CC=1C1(CC)CCC(=O)NC1=O ROBVIMPUHSLWNV-UHFFFAOYSA-N 0.000 description 2
- 229960003437 aminoglutethimide Drugs 0.000 description 2
- 230000003321 amplification Effects 0.000 description 2
- 239000003098 androgen Substances 0.000 description 2
- 229940030486 androgens Drugs 0.000 description 2
- 150000001450 anions Chemical class 0.000 description 2
- RGHILYZRVFRRNK-UHFFFAOYSA-N anthracene-1,2-dione Chemical compound C1=CC=C2C=C(C(C(=O)C=C3)=O)C3=CC2=C1 RGHILYZRVFRRNK-UHFFFAOYSA-N 0.000 description 2
- 230000002280 anti-androgenic effect Effects 0.000 description 2
- 229940046836 anti-estrogen Drugs 0.000 description 2
- 230000001833 anti-estrogenic effect Effects 0.000 description 2
- 239000000051 antiandrogen Substances 0.000 description 2
- 229940088710 antibiotic agent Drugs 0.000 description 2
- 230000005875 antibody response Effects 0.000 description 2
- 229940045687 antimetabolites folic acid analogs Drugs 0.000 description 2
- 229940045719 antineoplastic alkylating agent nitrosoureas Drugs 0.000 description 2
- 239000003963 antioxidant agent Substances 0.000 description 2
- 235000006708 antioxidants Nutrition 0.000 description 2
- 125000000328 arabinofuranosyl group Chemical group C1([C@@H](O)[C@H](O)[C@H](O1)CO)* 0.000 description 2
- FIVPIPIDMRVLAY-UHFFFAOYSA-N aspergillin Natural products C1C2=CC=CC(O)C2N2C1(SS1)C(=O)N(C)C1(CO)C2=O FIVPIPIDMRVLAY-UHFFFAOYSA-N 0.000 description 2
- FZCSTZYAHCUGEM-UHFFFAOYSA-N aspergillomarasmine B Natural products OC(=O)CNC(C(O)=O)CNC(C(O)=O)CC(O)=O FZCSTZYAHCUGEM-UHFFFAOYSA-N 0.000 description 2
- 238000000376 autoradiography Methods 0.000 description 2
- VSRXQHXAPYXROS-UHFFFAOYSA-N azanide;cyclobutane-1,1-dicarboxylic acid;platinum(2+) Chemical compound [NH2-].[NH2-].[Pt+2].OC(=O)C1(C(O)=O)CCC1 VSRXQHXAPYXROS-UHFFFAOYSA-N 0.000 description 2
- 238000010533 azeotropic distillation Methods 0.000 description 2
- 125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 description 2
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 2
- ZVSKZLHKADLHSD-UHFFFAOYSA-N benzanilide Chemical class C=1C=CC=CC=1C(=O)NC1=CC=CC=C1 ZVSKZLHKADLHSD-UHFFFAOYSA-N 0.000 description 2
- 150000001556 benzimidazoles Chemical class 0.000 description 2
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 2
- 239000003613 bile acid Substances 0.000 description 2
- 230000003115 biocidal effect Effects 0.000 description 2
- 229960001561 bleomycin Drugs 0.000 description 2
- OYVAGSVQBOHSSS-UAPAGMARSA-O bleomycin A2 Chemical compound N([C@H](C(=O)N[C@H](C)[C@@H](O)[C@H](C)C(=O)N[C@@H]([C@H](O)C)C(=O)NCCC=1SC=C(N=1)C=1SC=C(N=1)C(=O)NCCC[S+](C)C)[C@@H](O[C@H]1[C@H]([C@@H](O)[C@H](O)[C@H](CO)O1)O[C@@H]1[C@H]([C@@H](OC(N)=O)[C@H](O)[C@@H](CO)O1)O)C=1N=CNC=1)C(=O)C1=NC([C@H](CC(N)=O)NC[C@H](N)C(N)=O)=NC(N)=C1C OYVAGSVQBOHSSS-UAPAGMARSA-O 0.000 description 2
- 210000004204 blood vessel Anatomy 0.000 description 2
- ZADPBFCGQRWHPN-UHFFFAOYSA-N boronic acid Chemical compound OBO ZADPBFCGQRWHPN-UHFFFAOYSA-N 0.000 description 2
- 229960002092 busulfan Drugs 0.000 description 2
- GVEZIHKRYBHEFX-UHFFFAOYSA-N caerulein A Natural products CC=CCC=CCCC(=O)C1OC1C(N)=O GVEZIHKRYBHEFX-UHFFFAOYSA-N 0.000 description 2
- 239000011575 calcium Substances 0.000 description 2
- 229910052791 calcium Inorganic materials 0.000 description 2
- 239000004202 carbamide Substances 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- 229960004562 carboplatin Drugs 0.000 description 2
- 208000002458 carcinoid tumor Diseases 0.000 description 2
- 229960005243 carmustine Drugs 0.000 description 2
- 238000000423 cell based assay Methods 0.000 description 2
- 230000024245 cell differentiation Effects 0.000 description 2
- 230000003833 cell viability Effects 0.000 description 2
- GVEZIHKRYBHEFX-NQQPLRFYSA-N cerulenin Chemical compound C\C=C\C\C=C\CCC(=O)[C@H]1O[C@H]1C(N)=O GVEZIHKRYBHEFX-NQQPLRFYSA-N 0.000 description 2
- 229950005984 cerulenin Drugs 0.000 description 2
- 229960004630 chlorambucil Drugs 0.000 description 2
- JCKYGMPEJWAADB-UHFFFAOYSA-N chlorambucil Chemical compound OC(=O)CCCC1=CC=C(N(CCCl)CCCl)C=C1 JCKYGMPEJWAADB-UHFFFAOYSA-N 0.000 description 2
- 208000032852 chronic lymphocytic leukemia Diseases 0.000 description 2
- 229960003405 ciprofloxacin Drugs 0.000 description 2
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 2
- 229960004316 cisplatin Drugs 0.000 description 2
- 238000004891 communication Methods 0.000 description 2
- 239000000470 constituent Substances 0.000 description 2
- LXWYCLOUQZZDBD-LIYNQYRNSA-N csfv Chemical compound C([C@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)[C@@H](C)CC)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(O)=O)C1=CC=C(O)C=C1 LXWYCLOUQZZDBD-LIYNQYRNSA-N 0.000 description 2
- 125000004093 cyano group Chemical group *C#N 0.000 description 2
- 229960004397 cyclophosphamide Drugs 0.000 description 2
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 2
- 229960000684 cytarabine Drugs 0.000 description 2
- 231100000433 cytotoxic Toxicity 0.000 description 2
- 230000001472 cytotoxic effect Effects 0.000 description 2
- 229960003901 dacarbazine Drugs 0.000 description 2
- 230000006196 deacetylation Effects 0.000 description 2
- 238000003381 deacetylation reaction Methods 0.000 description 2
- 230000034994 death Effects 0.000 description 2
- 238000010908 decantation Methods 0.000 description 2
- 238000005695 dehalogenation reaction Methods 0.000 description 2
- CFCUWKMKBJTWLW-UHFFFAOYSA-N deoliosyl-3C-alpha-L-digitoxosyl-MTM Natural products CC=1C(O)=C2C(O)=C3C(=O)C(OC4OC(C)C(O)C(OC5OC(C)C(O)C(OC6OC(C)C(O)C(C)(O)C6)C5)C4)C(C(OC)C(=O)C(O)C(C)O)CC3=CC2=CC=1OC(OC(C)C1O)CC1OC1CC(O)C(O)C(C)O1 CFCUWKMKBJTWLW-UHFFFAOYSA-N 0.000 description 2
- 238000005828 desilylation reaction Methods 0.000 description 2
- YNHIGQDRGKUECZ-UHFFFAOYSA-N dichloropalladium;triphenylphosphanium Chemical compound Cl[Pd]Cl.C1=CC=CC=C1[PH+](C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1[PH+](C=1C=CC=CC=1)C1=CC=CC=C1 YNHIGQDRGKUECZ-UHFFFAOYSA-N 0.000 description 2
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 2
- 229940042399 direct acting antivirals protease inhibitors Drugs 0.000 description 2
- PRAKJMSDJKAYCZ-UHFFFAOYSA-N dodecahydrosqualene Natural products CC(C)CCCC(C)CCCC(C)CCCCC(C)CCCC(C)CCCC(C)C PRAKJMSDJKAYCZ-UHFFFAOYSA-N 0.000 description 2
- 231100000673 dose–response relationship Toxicity 0.000 description 2
- 229960004679 doxorubicin Drugs 0.000 description 2
- 238000009510 drug design Methods 0.000 description 2
- 239000012039 electrophile Substances 0.000 description 2
- 239000003480 eluent Substances 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 210000003238 esophagus Anatomy 0.000 description 2
- 230000032050 esterification Effects 0.000 description 2
- 238000005886 esterification reaction Methods 0.000 description 2
- 229940011871 estrogen Drugs 0.000 description 2
- 239000000262 estrogen Substances 0.000 description 2
- 239000000328 estrogen antagonist Substances 0.000 description 2
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 description 2
- 229960002568 ethinylestradiol Drugs 0.000 description 2
- VJJPUSNTGOMMGY-MRVIYFEKSA-N etoposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@H](C)OC[C@H]4O3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 VJJPUSNTGOMMGY-MRVIYFEKSA-N 0.000 description 2
- 229960005420 etoposide Drugs 0.000 description 2
- 238000011156 evaluation Methods 0.000 description 2
- 230000002349 favourable effect Effects 0.000 description 2
- 238000000855 fermentation Methods 0.000 description 2
- 230000004151 fermentation Effects 0.000 description 2
- 229960000961 floxuridine Drugs 0.000 description 2
- XRECTZIEBJDKEO-UHFFFAOYSA-N flucytosine Chemical compound NC1=NC(=O)NC=C1F XRECTZIEBJDKEO-UHFFFAOYSA-N 0.000 description 2
- MKXKFYHWDHIYRV-UHFFFAOYSA-N flutamide Chemical compound CC(C)C(=O)NC1=CC=C([N+]([O-])=O)C(C(F)(F)F)=C1 MKXKFYHWDHIYRV-UHFFFAOYSA-N 0.000 description 2
- 229960002074 flutamide Drugs 0.000 description 2
- 150000002224 folic acids Chemical class 0.000 description 2
- 108020001507 fusion proteins Proteins 0.000 description 2
- 102000037865 fusion proteins Human genes 0.000 description 2
- WIGCFUFOHFEKBI-UHFFFAOYSA-N gamma-tocopherol Natural products CC(C)CCCC(C)CCCC(C)CCCC1CCC2C(C)C(O)C(C)C(C)C2O1 WIGCFUFOHFEKBI-UHFFFAOYSA-N 0.000 description 2
- FIVPIPIDMRVLAY-RBJBARPLSA-N gliotoxin Chemical compound C1C2=CC=C[C@H](O)[C@H]2N2[C@]1(SS1)C(=O)N(C)[C@@]1(CO)C2=O FIVPIPIDMRVLAY-RBJBARPLSA-N 0.000 description 2
- 229940103893 gliotoxin Drugs 0.000 description 2
- 229930190252 gliotoxin Natural products 0.000 description 2
- XLXSAKCOAKORKW-AQJXLSMYSA-N gonadorelin Chemical class C([C@@H](C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N1[C@@H](CCC1)C(=O)NCC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H]1NC(=O)CC1)C1=CC=C(O)C=C1 XLXSAKCOAKORKW-AQJXLSMYSA-N 0.000 description 2
- RQFCJASXJCIDSX-UUOKFMHZSA-N guanosine 5'-monophosphate Chemical compound C1=2NC(N)=NC(=O)C=2N=CN1[C@@H]1O[C@H](COP(O)(O)=O)[C@@H](O)[C@H]1O RQFCJASXJCIDSX-UUOKFMHZSA-N 0.000 description 2
- 238000003306 harvesting Methods 0.000 description 2
- 230000036541 health Effects 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 230000002440 hepatic effect Effects 0.000 description 2
- 208000006454 hepatitis Diseases 0.000 description 2
- 231100000283 hepatitis Toxicity 0.000 description 2
- UUVWYPNAQBNQJQ-UHFFFAOYSA-N hexamethylmelamine Chemical compound CN(C)C1=NC(N(C)C)=NC(N(C)C)=N1 UUVWYPNAQBNQJQ-UHFFFAOYSA-N 0.000 description 2
- FUZZWVXGSFPDMH-UHFFFAOYSA-M hexanoate Chemical compound CCCCCC([O-])=O FUZZWVXGSFPDMH-UHFFFAOYSA-M 0.000 description 2
- 238000002000 high resolution fast-atom bombardment mass spectrometry Methods 0.000 description 2
- 229960001330 hydroxycarbamide Drugs 0.000 description 2
- 230000003463 hyperproliferative effect Effects 0.000 description 2
- JGJLWPGRMCADHB-UHFFFAOYSA-N hypobromite Inorganic materials Br[O-] JGJLWPGRMCADHB-UHFFFAOYSA-N 0.000 description 2
- CUILPNURFADTPE-UHFFFAOYSA-N hypobromous acid Chemical compound BrO CUILPNURFADTPE-UHFFFAOYSA-N 0.000 description 2
- 229960001101 ifosfamide Drugs 0.000 description 2
- HOMGKSMUEGBAAB-UHFFFAOYSA-N ifosfamide Chemical compound ClCCNP1(=O)OCCCN1CCCl HOMGKSMUEGBAAB-UHFFFAOYSA-N 0.000 description 2
- 238000002649 immunization Methods 0.000 description 2
- 230000003053 immunization Effects 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 230000001939 inductive effect Effects 0.000 description 2
- 230000002458 infectious effect Effects 0.000 description 2
- 150000007529 inorganic bases Chemical class 0.000 description 2
- 229950000038 interferon alfa Drugs 0.000 description 2
- 230000009545 invasion Effects 0.000 description 2
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 2
- 230000003902 lesion Effects 0.000 description 2
- GFIJNRVAKGFPGQ-LIJARHBVSA-N leuprolide Chemical compound CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](CC(C)C)NC(=O)[C@@H](NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H]1NC(=O)CC1)CC1=CC=C(O)C=C1 GFIJNRVAKGFPGQ-LIJARHBVSA-N 0.000 description 2
- 229960004338 leuprorelin Drugs 0.000 description 2
- 229960003376 levofloxacin Drugs 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 229960002247 lomustine Drugs 0.000 description 2
- 208000020816 lung neoplasm Diseases 0.000 description 2
- 201000000564 macroglobulinemia Diseases 0.000 description 2
- 229920002521 macromolecule Polymers 0.000 description 2
- 239000011777 magnesium Substances 0.000 description 2
- 229910052749 magnesium Inorganic materials 0.000 description 2
- NUJOXMJBOLGQSY-UHFFFAOYSA-N manganese dioxide Chemical compound O=[Mn]=O NUJOXMJBOLGQSY-UHFFFAOYSA-N 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- 229960004961 mechlorethamine Drugs 0.000 description 2
- HAWPXGHAZFHHAD-UHFFFAOYSA-N mechlorethamine Chemical compound ClCCN(C)CCCl HAWPXGHAZFHHAD-UHFFFAOYSA-N 0.000 description 2
- 239000002609 medium Substances 0.000 description 2
- 229960002985 medroxyprogesterone acetate Drugs 0.000 description 2
- PSGAAPLEWMOORI-PEINSRQWSA-N medroxyprogesterone acetate Chemical compound C([C@@]12C)CC(=O)C=C1[C@@H](C)C[C@@H]1[C@@H]2CC[C@]2(C)[C@@](OC(C)=O)(C(C)=O)CC[C@H]21 PSGAAPLEWMOORI-PEINSRQWSA-N 0.000 description 2
- 229960004296 megestrol acetate Drugs 0.000 description 2
- RQZAXGRLVPAYTJ-GQFGMJRRSA-N megestrol acetate Chemical compound C1=C(C)C2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(C)=O)(OC(=O)C)[C@@]1(C)CC2 RQZAXGRLVPAYTJ-GQFGMJRRSA-N 0.000 description 2
- 229960001924 melphalan Drugs 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 230000009401 metastasis Effects 0.000 description 2
- 150000004702 methyl esters Chemical class 0.000 description 2
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 2
- 230000002438 mitochondrial effect Effects 0.000 description 2
- 229960000350 mitotane Drugs 0.000 description 2
- XJYUBGDTTVGRLD-UHFFFAOYSA-N n-(5-benzyl-2-oxo-1h-pyrimidin-6-yl)-4-methoxybenzamide Chemical compound C1=CC(OC)=CC=C1C(=O)NC1=C(CC=2C=CC=CC=2)C=NC(=O)N1 XJYUBGDTTVGRLD-UHFFFAOYSA-N 0.000 description 2
- DPXGTRKHHGOESS-UHFFFAOYSA-N n-(5-ethyl-2-oxo-1h-pyrimidin-6-yl)-4-methoxybenzamide Chemical compound C1=NC(=O)NC(NC(=O)C=2C=CC(OC)=CC=2)=C1CC DPXGTRKHHGOESS-UHFFFAOYSA-N 0.000 description 2
- 125000001624 naphthyl group Chemical group 0.000 description 2
- 230000003472 neutralizing effect Effects 0.000 description 2
- 231100000252 nontoxic Toxicity 0.000 description 2
- 230000003000 nontoxic effect Effects 0.000 description 2
- 238000003199 nucleic acid amplification method Methods 0.000 description 2
- 150000007523 nucleic acids Chemical class 0.000 description 2
- 239000012038 nucleophile Substances 0.000 description 2
- 230000000269 nucleophilic effect Effects 0.000 description 2
- 229960001699 ofloxacin Drugs 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- 230000003287 optical effect Effects 0.000 description 2
- 150000007530 organic bases Chemical class 0.000 description 2
- 230000008520 organization Effects 0.000 description 2
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 description 2
- 230000002188 osteogenic effect Effects 0.000 description 2
- 229910052763 palladium Inorganic materials 0.000 description 2
- 208000021255 pancreatic insulinoma Diseases 0.000 description 2
- 229960002340 pentostatin Drugs 0.000 description 2
- FPVKHBSQESCIEP-JQCXWYLXSA-N pentostatin Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(N=CNC[C@H]2O)=C2N=C1 FPVKHBSQESCIEP-JQCXWYLXSA-N 0.000 description 2
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 2
- NAYYNDKKHOIIOD-UHFFFAOYSA-N phthalamide Chemical class NC(=O)C1=CC=CC=C1C(N)=O NAYYNDKKHOIIOD-UHFFFAOYSA-N 0.000 description 2
- 230000035479 physiological effects, processes and functions Effects 0.000 description 2
- 239000000902 placebo Substances 0.000 description 2
- 229940068196 placebo Drugs 0.000 description 2
- 229910052697 platinum Inorganic materials 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- XOFYZVNMUHMLCC-ZPOLXVRWSA-N prednisone Chemical compound O=C1C=C[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 XOFYZVNMUHMLCC-ZPOLXVRWSA-N 0.000 description 2
- 229960004618 prednisone Drugs 0.000 description 2
- 229960000624 procarbazine Drugs 0.000 description 2
- 239000000583 progesterone congener Substances 0.000 description 2
- 230000002062 proliferating effect Effects 0.000 description 2
- 230000000069 prophylactic effect Effects 0.000 description 2
- 235000019419 proteases Nutrition 0.000 description 2
- 150000003212 purines Chemical class 0.000 description 2
- 150000003230 pyrimidines Chemical class 0.000 description 2
- 238000010791 quenching Methods 0.000 description 2
- 230000000171 quenching effect Effects 0.000 description 2
- 150000007660 quinolones Chemical class 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 210000002345 respiratory system Anatomy 0.000 description 2
- 238000004007 reversed phase HPLC Methods 0.000 description 2
- 238000012552 review Methods 0.000 description 2
- 206010039073 rheumatoid arthritis Diseases 0.000 description 2
- 108091092562 ribozyme Proteins 0.000 description 2
- 229960000888 rimantadine Drugs 0.000 description 2
- 229920002477 rna polymer Polymers 0.000 description 2
- 231100000241 scar Toxicity 0.000 description 2
- 238000002821 scintillation proximity assay Methods 0.000 description 2
- JPJALAQPGMAKDF-UHFFFAOYSA-N selenium dioxide Chemical compound O=[Se]=O JPJALAQPGMAKDF-UHFFFAOYSA-N 0.000 description 2
- 210000002966 serum Anatomy 0.000 description 2
- 238000006884 silylation reaction Methods 0.000 description 2
- 206010040882 skin lesion Diseases 0.000 description 2
- 231100000444 skin lesion Toxicity 0.000 description 2
- 150000003384 small molecules Chemical class 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 238000002415 sodium dodecyl sulfate polyacrylamide gel electrophoresis Methods 0.000 description 2
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 2
- 235000019345 sodium thiosulphate Nutrition 0.000 description 2
- 210000004872 soft tissue Anatomy 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 229940031439 squalene Drugs 0.000 description 2
- TUHBEKDERLKLEC-UHFFFAOYSA-N squalene Natural products CC(=CCCC(=CCCC(=CCCC=C(/C)CCC=C(/C)CC=C(C)C)C)C)C TUHBEKDERLKLEC-UHFFFAOYSA-N 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 239000008223 sterile water Substances 0.000 description 2
- 239000012258 stirred mixture Substances 0.000 description 2
- 238000007920 subcutaneous administration Methods 0.000 description 2
- 150000008163 sugars Chemical class 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- 229920001059 synthetic polymer Polymers 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- 229960001603 tamoxifen Drugs 0.000 description 2
- NRUKOCRGYNPUPR-QBPJDGROSA-N teniposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@@H](OC[C@H]4O3)C=3SC=CC=3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 NRUKOCRGYNPUPR-QBPJDGROSA-N 0.000 description 2
- 229960001278 teniposide Drugs 0.000 description 2
- MHYGQXWCZAYSLJ-UHFFFAOYSA-N tert-butyl-chloro-diphenylsilane Chemical compound C=1C=CC=CC=1[Si](Cl)(C(C)(C)C)C1=CC=CC=C1 MHYGQXWCZAYSLJ-UHFFFAOYSA-N 0.000 description 2
- 229960001712 testosterone propionate Drugs 0.000 description 2
- DLYUQMMRRRQYAE-UHFFFAOYSA-N tetraphosphorus decaoxide Chemical compound O1P(O2)(=O)OP3(=O)OP1(=O)OP2(=O)O3 DLYUQMMRRRQYAE-UHFFFAOYSA-N 0.000 description 2
- RYYWUUFWQRZTIU-UHFFFAOYSA-K thiophosphate Chemical compound [O-]P([O-])([O-])=S RYYWUUFWQRZTIU-UHFFFAOYSA-K 0.000 description 2
- 229960001196 thiotepa Drugs 0.000 description 2
- 150000004654 triazenes Chemical class 0.000 description 2
- NTJBWZHVSJNKAD-UHFFFAOYSA-N triethylazanium;fluoride Chemical compound [F-].CC[NH+](CC)CC NTJBWZHVSJNKAD-UHFFFAOYSA-N 0.000 description 2
- WJKHJLXJJJATHN-UHFFFAOYSA-N triflic anhydride Chemical compound FC(F)(F)S(=O)(=O)OS(=O)(=O)C(F)(F)F WJKHJLXJJJATHN-UHFFFAOYSA-N 0.000 description 2
- FTVLMFQEYACZNP-UHFFFAOYSA-N trimethylsilyl trifluoromethanesulfonate Chemical compound C[Si](C)(C)OS(=O)(=O)C(F)(F)F FTVLMFQEYACZNP-UHFFFAOYSA-N 0.000 description 2
- JBWKIWSBJXDJDT-UHFFFAOYSA-N triphenylmethyl chloride Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(Cl)C1=CC=CC=C1 JBWKIWSBJXDJDT-UHFFFAOYSA-N 0.000 description 2
- 229910052721 tungsten Inorganic materials 0.000 description 2
- 150000003672 ureas Chemical class 0.000 description 2
- 229960003048 vinblastine Drugs 0.000 description 2
- OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-XQKSVPLYSA-N 0.000 description 2
- 229960004528 vincristine Drugs 0.000 description 2
- OGWKCGZFUXNPDA-UHFFFAOYSA-N vincristine Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(OC(C)=O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-UHFFFAOYSA-N 0.000 description 2
- 201000001862 viral hepatitis Diseases 0.000 description 2
- 230000000007 visual effect Effects 0.000 description 2
- 235000019165 vitamin E Nutrition 0.000 description 2
- 229940046009 vitamin E Drugs 0.000 description 2
- 239000011709 vitamin E Substances 0.000 description 2
- 229940051021 yellow-fever virus Drugs 0.000 description 2
- ARAIBEBZBOPLMB-UFGQHTETSA-N zanamivir Chemical compound CC(=O)N[C@@H]1[C@@H](N=C(N)N)C=C(C(O)=O)O[C@H]1[C@H](O)[C@H](O)CO ARAIBEBZBOPLMB-UFGQHTETSA-N 0.000 description 2
- UAOUIVVJBYDFKD-XKCDOFEDSA-N (1R,9R,10S,11R,12R,15S,18S,21R)-10,11,21-trihydroxy-8,8-dimethyl-14-methylidene-4-(prop-2-enylamino)-20-oxa-5-thia-3-azahexacyclo[9.7.2.112,15.01,9.02,6.012,18]henicosa-2(6),3-dien-13-one Chemical compound C([C@@H]1[C@@H](O)[C@@]23C(C1=C)=O)C[C@H]2[C@]12C(N=C(NCC=C)S4)=C4CC(C)(C)[C@H]1[C@H](O)[C@]3(O)OC2 UAOUIVVJBYDFKD-XKCDOFEDSA-N 0.000 description 1
- ABJSOROVZZKJGI-OCYUSGCXSA-N (1r,2r,4r)-2-(4-bromophenyl)-n-[(4-chlorophenyl)-(2-fluoropyridin-4-yl)methyl]-4-morpholin-4-ylcyclohexane-1-carboxamide Chemical compound C1=NC(F)=CC(C(NC(=O)[C@H]2[C@@H](C[C@@H](CC2)N2CCOCC2)C=2C=CC(Br)=CC=2)C=2C=CC(Cl)=CC=2)=C1 ABJSOROVZZKJGI-OCYUSGCXSA-N 0.000 description 1
- XUGWUUDOWNZAGW-VDAHYXPESA-N (1s,2r,5r)-5-(6-aminopurin-9-yl)-3-(hydroxymethyl)cyclopent-3-ene-1,2-diol Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1C=C(CO)[C@@H](O)[C@H]1O XUGWUUDOWNZAGW-VDAHYXPESA-N 0.000 description 1
- SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical compound O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-N 0.000 description 1
- COJAFGBATFHLAB-FTWQFJAYSA-N (2r,3r,4r,5r)-2-(2,6-dichloropurin-1-yl)-5-(hydroxymethyl)oxolane-3,4-diol Chemical compound O[C@@H]1[C@@H](O)[C@@H](CO)O[C@H]1N1C(Cl)=C2N=CN=C2N=C1Cl COJAFGBATFHLAB-FTWQFJAYSA-N 0.000 description 1
- YGGPSENVQAHYFZ-GAWUUDPSSA-N (2r,3r,4r,5r)-2-(6-chloropurin-1-yl)-5-(hydroxymethyl)oxolane-3,4-diol Chemical compound O[C@@H]1[C@@H](O)[C@@H](CO)O[C@H]1N1C(Cl)=C2N=CN=C2N=C1 YGGPSENVQAHYFZ-GAWUUDPSSA-N 0.000 description 1
- GWKXCZZRPVJDQG-AMCGLFBUSA-N (2r,3r,4r,5r)-2-(hydroxymethyl)-5-(6-methylsulfanylpurin-1-yl)oxolane-3,4-diol Chemical compound C1=NC2=NC=NC2=C(SC)N1[C@@H]1O[C@H](CO)[C@H](O)[C@H]1O GWKXCZZRPVJDQG-AMCGLFBUSA-N 0.000 description 1
- ZCHDHSNPYVRWNT-MTQIGAJGSA-N (2r,3r,5s)-2-(2-aminopurin-9-yl)-5-(hydroxymethyl)oxolan-3-ol Chemical compound C12=NC(N)=NC=C2N=CN1[C@@H]1O[C@H](CO)C[C@H]1O ZCHDHSNPYVRWNT-MTQIGAJGSA-N 0.000 description 1
- ODFGMUBHRZHCSC-NYNCVSEMSA-N (2r,3r,5s)-5-(hydroxymethyl)-2-(6-methoxypurin-1-yl)oxolan-3-ol Chemical compound C1=NC2=NC=NC2=C(OC)N1[C@@H]1O[C@H](CO)C[C@H]1O ODFGMUBHRZHCSC-NYNCVSEMSA-N 0.000 description 1
- HMAYWFDBODIZHU-GQTRHBFLSA-N (2r,3s,4r,5r)-2-(2-amino-6-methylsulfanylpurin-9-yl)-5-(hydroxymethyl)-4-iodooxolan-3-ol Chemical compound C1=NC=2C(SC)=NC(N)=NC=2N1[C@@H]1O[C@H](CO)[C@H](I)[C@H]1O HMAYWFDBODIZHU-GQTRHBFLSA-N 0.000 description 1
- OISWIMRZJWVCOV-GQTRHBFLSA-N (2r,3s,4r,5r)-2-(6-aminopurin-9-yl)-5-(hydroxymethyl)-4-iodooxolan-3-ol Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@H](I)[C@H]1O OISWIMRZJWVCOV-GQTRHBFLSA-N 0.000 description 1
- QQBWNALIEFISIK-WCGPTHBMSA-N (2r,3s,4r,5r)-5-(hydroxymethyl)-4-iodo-2-(6-methoxypurin-9-yl)oxolan-3-ol Chemical compound C1=NC=2C(OC)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@H](I)[C@H]1O QQBWNALIEFISIK-WCGPTHBMSA-N 0.000 description 1
- DTVATLQCFYBIRP-WCGPTHBMSA-N (2r,3s,4r,5r)-5-(hydroxymethyl)-4-iodo-2-(6-methylsulfanylpurin-9-yl)oxolan-3-ol Chemical compound C1=NC=2C(SC)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@H](I)[C@H]1O DTVATLQCFYBIRP-WCGPTHBMSA-N 0.000 description 1
- VIJSPAIQWVPKQZ-BLECARSGSA-N (2s)-2-[[(2s)-2-[[(2s)-2-[[(2s)-2-[[(2s)-2-[[(2s)-2-acetamido-5-(diaminomethylideneamino)pentanoyl]amino]-4-methylpentanoyl]amino]-4,4-dimethylpentanoyl]amino]-4-methylpentanoyl]amino]propanoyl]amino]-5-(diaminomethylideneamino)pentanoic acid Chemical class NC(=N)NCCC[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(C)(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCNC(N)=N)NC(C)=O VIJSPAIQWVPKQZ-BLECARSGSA-N 0.000 description 1
- UKUOWIYWMMABNI-FYGVXOAGSA-N (3R,5S)-5-(hydroxymethyl)oxolane-2,3-diol Chemical class OC[C@@H]1C[C@@H](O)C(O)O1.OC[C@@H]1C[C@@H](O)C(O)O1 UKUOWIYWMMABNI-FYGVXOAGSA-N 0.000 description 1
- JAUQZVBVVJJRKM-XZBKPIIZSA-N (3ar,5r,6s,6ar)-5-(hydroxymethyl)-2,2-dimethyl-3a,5,6,6a-tetrahydrofuro[2,3-d][1,3]dioxol-6-ol Chemical compound O1[C@H](CO)[C@H](O)[C@H]2OC(C)(C)O[C@H]21 JAUQZVBVVJJRKM-XZBKPIIZSA-N 0.000 description 1
- ZUYIBYOYYUXIGY-PYHARJCCSA-N (3r,5s)-5-(hydroxymethyl)oxolane-2,3-diol Chemical group OC[C@@H]1C[C@@H](O)C(O)O1 ZUYIBYOYYUXIGY-PYHARJCCSA-N 0.000 description 1
- XPIJMQVLTXAGME-UHFFFAOYSA-N 1,1-dimethoxycyclohexane Chemical compound COC1(OC)CCCCC1 XPIJMQVLTXAGME-UHFFFAOYSA-N 0.000 description 1
- CUJPFPXNDSIBPG-UHFFFAOYSA-N 1,3-propanediyl Chemical group [CH2]C[CH2] CUJPFPXNDSIBPG-UHFFFAOYSA-N 0.000 description 1
- OMIVCRYZSXDGAB-UHFFFAOYSA-N 1,4-butanediyl Chemical group [CH2]CC[CH2] OMIVCRYZSXDGAB-UHFFFAOYSA-N 0.000 description 1
- JRPKWAOJQDQYQT-ZKYQVNSYSA-N 1-[(2R,3R,5S)-3-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-6-phenyl-2-sulfanylidenepyrimidin-4-one Chemical compound C1(=CC=CC=C1)C1=CC(NC(N1[C@H]1[C@H](O)C[C@@H](CO)O1)=S)=O JRPKWAOJQDQYQT-ZKYQVNSYSA-N 0.000 description 1
- LLXDMZAIHRZCFL-FDDDBJFASA-N 1-[(2r,3r,4r,5r)-4-hydroxy-5-(hydroxymethyl)-3-iodooxolan-2-yl]-5-(2-iodoethenyl)pyrimidine-2,4-dione Chemical compound I[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(C=CI)=C1 LLXDMZAIHRZCFL-FDDDBJFASA-N 0.000 description 1
- DXUWEFSLVGBCTF-UAKXSSHOSA-N 1-[(2r,3r,4r,5r)-4-hydroxy-5-(hydroxymethyl)-3-iodooxolan-2-yl]-5-iodopyrimidine-2,4-dione Chemical compound I[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(I)=C1 DXUWEFSLVGBCTF-UAKXSSHOSA-N 0.000 description 1
- PTWBTVJPKOHDJU-JXOAFFINSA-N 1-[(2r,3r,4r,5r)-4-hydroxy-5-(hydroxymethyl)-3-iodooxolan-2-yl]-5-methylpyrimidine-2,4-dione Chemical compound O=C1NC(=O)C(C)=CN1[C@H]1[C@H](I)[C@H](O)[C@@H](CO)O1 PTWBTVJPKOHDJU-JXOAFFINSA-N 0.000 description 1
- TVVXLDCSZOWZDW-TURQNECASA-N 1-[(2r,3r,4r,5r)-4-hydroxy-5-(hydroxymethyl)-3-iodooxolan-2-yl]-5-propylpyrimidine-2,4-dione Chemical compound O=C1NC(=O)C(CCC)=CN1[C@H]1[C@H](I)[C@H](O)[C@@H](CO)O1 TVVXLDCSZOWZDW-TURQNECASA-N 0.000 description 1
- FIAQJMSWEWAREU-JXOAFFINSA-N 1-[(2r,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-4-(hydroxyamino)-5-methylpyrimidin-2-one Chemical compound O=C1N=C(NO)C(C)=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 FIAQJMSWEWAREU-JXOAFFINSA-N 0.000 description 1
- GSKWXRBRDHHXFE-HKUMRIAESA-N 1-[(2r,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-4-(hydroxyamino)-5-phenylpyrimidin-2-one Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)N=C(NO)C(C=2C=CC=CC=2)=C1 GSKWXRBRDHHXFE-HKUMRIAESA-N 0.000 description 1
- ZGDBEMXXLCQUGR-FDDDBJFASA-N 1-[(2r,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-5-ethenyl-4-(hydroxyamino)pyrimidin-2-one Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)N=C(NO)C(C=C)=C1 ZGDBEMXXLCQUGR-FDDDBJFASA-N 0.000 description 1
- RHNKTNRPTOLWJS-FDDDBJFASA-N 1-[(2r,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-5-ethenylpyrimidine-2,4-dione Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(C=C)=C1 RHNKTNRPTOLWJS-FDDDBJFASA-N 0.000 description 1
- UERJERREQCRKCZ-FDDDBJFASA-N 1-[(2r,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-5-ethyl-4-(hydroxyamino)pyrimidin-2-one Chemical compound O=C1N=C(NO)C(CC)=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 UERJERREQCRKCZ-FDDDBJFASA-N 0.000 description 1
- GXQQIXPGOMTEHQ-FDDDBJFASA-N 1-[(2r,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-5-ethynyl-4-(hydroxyamino)pyrimidin-2-one Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)N=C(NO)C(C#C)=C1 GXQQIXPGOMTEHQ-FDDDBJFASA-N 0.000 description 1
- QCWBIPKYTBFWHH-FDDDBJFASA-N 1-[(2r,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-5-ethynylpyrimidine-2,4-dione Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(C#C)=C1 QCWBIPKYTBFWHH-FDDDBJFASA-N 0.000 description 1
- FBGTUUWFXKRMTO-UAKXSSHOSA-N 1-[(2r,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-5-fluoro-4-(hydroxyamino)pyrimidin-2-one Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=NO)C(F)=C1 FBGTUUWFXKRMTO-UAKXSSHOSA-N 0.000 description 1
- VFIJIKXOVPALRF-PJDOXKJDSA-N 1-[(2r,3r,5s)-3-(oxan-2-yloxy)-5-(oxan-2-yloxymethyl)oxolan-2-yl]pyrimidine-2,4-dione Chemical compound O=C1NC(=O)C=CN1[C@H]1[C@H](OC2OCCCC2)C[C@@H](COC2OCCCC2)O1 VFIJIKXOVPALRF-PJDOXKJDSA-N 0.000 description 1
- CSLWEKZOADIDHQ-CVTKMRTPSA-N 1-[(2r,3r,5s)-3-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-5-(trifluoromethyl)pyrimidine-2,4-dione Chemical compound O1[C@H](CO)C[C@@H](O)[C@@H]1N1C(=O)NC(=O)C(C(F)(F)F)=C1 CSLWEKZOADIDHQ-CVTKMRTPSA-N 0.000 description 1
- FXSQHDHBPJQTMY-FJGDRVTGSA-N 1-[(2r,3s,4r,5r)-3,4-dihydroxy-5-(hydroxymethyl)-3-iodooxolan-2-yl]pyrimidine-2,4-dione Chemical class O[C@]1(I)[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C=C1 FXSQHDHBPJQTMY-FJGDRVTGSA-N 0.000 description 1
- BYLXMVKXFDQZOD-FPSVSHIKSA-N 1-[(2r,3s,4r,5r)-3,4-dihydroxy-5-(hydroxymethyl)-4-iodooxolan-2-yl]pyrimidine-2,4-dione Chemical class O[C@@H]1[C@](I)(O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C=C1 BYLXMVKXFDQZOD-FPSVSHIKSA-N 0.000 description 1
- VRAWDIJUNIEIJP-GFQSEFKGSA-N 1-[(2r,3s,4r,5r)-4-bromo-3-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-5-phenylpyrimidine-2,4-dione Chemical compound O[C@@H]1[C@@H](Br)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(C=2C=CC=CC=2)=C1 VRAWDIJUNIEIJP-GFQSEFKGSA-N 0.000 description 1
- AKCXDCKGYQZTMA-FDDDBJFASA-N 1-[(2r,3s,4s,5r)-3-hydroxy-5-(hydroxymethyl)-4-iodooxolan-2-yl]-5-(2-iodoethenyl)pyrimidine-2,4-dione Chemical compound O[C@@H]1[C@H](I)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(C=CI)=C1 AKCXDCKGYQZTMA-FDDDBJFASA-N 0.000 description 1
- YBXPODJHDHGIBQ-UAKXSSHOSA-N 1-[(2r,3s,4s,5r)-3-hydroxy-5-(hydroxymethyl)-4-iodooxolan-2-yl]-5-iodopyrimidine-2,4-dione Chemical compound O[C@@H]1[C@H](I)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(I)=C1 YBXPODJHDHGIBQ-UAKXSSHOSA-N 0.000 description 1
- HFBUBUCFUZNYES-JXOAFFINSA-N 1-[(2r,3s,4s,5r)-3-hydroxy-5-(hydroxymethyl)-4-iodooxolan-2-yl]-5-methylpyrimidine-2,4-dione Chemical compound O=C1NC(=O)C(C)=CN1[C@H]1[C@H](O)[C@H](I)[C@@H](CO)O1 HFBUBUCFUZNYES-JXOAFFINSA-N 0.000 description 1
- SQIWMFNUSJGTKL-HKUMRIAESA-N 1-[(2r,3s,4s,5r)-3-hydroxy-5-(hydroxymethyl)-4-iodooxolan-2-yl]-5-phenylpyrimidine-2,4-dione Chemical compound O[C@@H]1[C@H](I)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(C=2C=CC=CC=2)=C1 SQIWMFNUSJGTKL-HKUMRIAESA-N 0.000 description 1
- XMOJQZGVVRHTMQ-XVFCMESISA-N 1-[(2r,3s,4s,5r)-4-bromo-3-hydroxy-5-(hydroxymethyl)oxolan-2-yl]pyrimidine-2,4-dione Chemical compound O[C@@H]1[C@H](Br)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C=C1 XMOJQZGVVRHTMQ-XVFCMESISA-N 0.000 description 1
- ZQXCQTAELHSNAT-UHFFFAOYSA-N 1-chloro-3-nitro-5-(trifluoromethyl)benzene Chemical compound [O-][N+](=O)C1=CC(Cl)=CC(C(F)(F)F)=C1 ZQXCQTAELHSNAT-UHFFFAOYSA-N 0.000 description 1
- QWENRTYMTSOGBR-UHFFFAOYSA-N 1H-1,2,3-Triazole Chemical compound C=1C=NNN=1 QWENRTYMTSOGBR-UHFFFAOYSA-N 0.000 description 1
- CXCHEKCRJQRVNG-UHFFFAOYSA-N 2,2,2-trifluoroethanesulfonyl chloride Chemical compound FC(F)(F)CS(Cl)(=O)=O CXCHEKCRJQRVNG-UHFFFAOYSA-N 0.000 description 1
- VMJNTFXCTXAXTC-UHFFFAOYSA-N 2,2-difluoro-1,3-benzodioxole-5-carbonitrile Chemical group C1=C(C#N)C=C2OC(F)(F)OC2=C1 VMJNTFXCTXAXTC-UHFFFAOYSA-N 0.000 description 1
- PHELOKYCCWVWFE-UHFFFAOYSA-N 2,2-dimethoxyacetic acid Chemical compound COC(OC)C(O)=O PHELOKYCCWVWFE-UHFFFAOYSA-N 0.000 description 1
- HEWZVZIVELJPQZ-UHFFFAOYSA-N 2,2-dimethoxypropane Chemical compound COC(C)(C)OC HEWZVZIVELJPQZ-UHFFFAOYSA-N 0.000 description 1
- HAUXRJCZDHHADG-UHFFFAOYSA-N 2,4-dioxo-1h-pyrimidine-5-carbonitrile Chemical class O=C1NC=C(C#N)C(=O)N1 HAUXRJCZDHHADG-UHFFFAOYSA-N 0.000 description 1
- YSUIQYOGTINQIN-UZFYAQMZSA-N 2-amino-9-[(1S,6R,8R,9S,10R,15R,17R,18R)-8-(6-aminopurin-9-yl)-9,18-difluoro-3,12-dihydroxy-3,12-bis(sulfanylidene)-2,4,7,11,13,16-hexaoxa-3lambda5,12lambda5-diphosphatricyclo[13.2.1.06,10]octadecan-17-yl]-1H-purin-6-one Chemical compound NC1=NC2=C(N=CN2[C@@H]2O[C@@H]3COP(S)(=O)O[C@@H]4[C@@H](COP(S)(=O)O[C@@H]2[C@@H]3F)O[C@H]([C@H]4F)N2C=NC3=C2N=CN=C3N)C(=O)N1 YSUIQYOGTINQIN-UZFYAQMZSA-N 0.000 description 1
- ZBDGHWFPLXXWRD-UHFFFAOYSA-N 2-methoxyoxane-3,4,5-triol Chemical compound COC1OCC(O)C(O)C1O ZBDGHWFPLXXWRD-UHFFFAOYSA-N 0.000 description 1
- CTRPRMNBTVRDFH-UHFFFAOYSA-N 2-n-methyl-1,3,5-triazine-2,4,6-triamine Chemical class CNC1=NC(N)=NC(N)=N1 CTRPRMNBTVRDFH-UHFFFAOYSA-N 0.000 description 1
- KPGXRSRHYNQIFN-UHFFFAOYSA-N 2-oxoglutaric acid Chemical compound OC(=O)CCC(=O)C(O)=O KPGXRSRHYNQIFN-UHFFFAOYSA-N 0.000 description 1
- GIIGHSIIKVOWKZ-UHFFFAOYSA-N 2h-triazolo[4,5-d]pyrimidine Chemical compound N1=CN=CC2=NNN=C21 GIIGHSIIKVOWKZ-UHFFFAOYSA-N 0.000 description 1
- 125000005809 3,4,5-trimethoxyphenyl group Chemical group [H]C1=C(OC([H])([H])[H])C(OC([H])([H])[H])=C(OC([H])([H])[H])C([H])=C1* 0.000 description 1
- JDXNXUZRMUBTSC-UHFFFAOYSA-N 3-(4-amino-4-benzoyl-2-oxo-1,3-dihydropyrimidin-5-yl)prop-2-enoic acid Chemical compound C(C1=CC=CC=C1)(=O)C1(NC(NC=C1C=CC(=O)O)=O)N JDXNXUZRMUBTSC-UHFFFAOYSA-N 0.000 description 1
- HZWIFUFWXLCDIM-UHFFFAOYSA-N 3-[(2-methylpropan-2-yl)oxymethyl]cyclopentane-1,2-diol Chemical compound CC(C)(C)OCC1CCC(O)C1O HZWIFUFWXLCDIM-UHFFFAOYSA-N 0.000 description 1
- WPDUAOZMVCPCQC-LKEWCRSYSA-N 3-[(2r,3r,5s)-3-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-2,6-dioxopyrimidine-4-carbaldehyde Chemical compound O1[C@H](CO)C[C@@H](O)[C@@H]1N1C(=O)NC(=O)C=C1C=O WPDUAOZMVCPCQC-LKEWCRSYSA-N 0.000 description 1
- OBERURODHNVESM-LKEWCRSYSA-N 3-[(2r,3r,5s)-3-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-2,6-dioxopyrimidine-4-carbonitrile Chemical compound O1[C@H](CO)C[C@@H](O)[C@@H]1N1C(=O)NC(=O)C=C1C#N OBERURODHNVESM-LKEWCRSYSA-N 0.000 description 1
- ZHHJEHIRDCCYBN-CVTKMRTPSA-N 3-[(2r,3r,5s)-3-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-2,6-dioxopyrimidine-4-carboxylic acid Chemical compound O1[C@H](CO)C[C@@H](O)[C@@H]1N1C(=O)NC(=O)C=C1C(O)=O ZHHJEHIRDCCYBN-CVTKMRTPSA-N 0.000 description 1
- MIGXLQAFFHEHNT-PNHWDRBUSA-N 3-[1-[(2r,3r,4r,5r)-4-hydroxy-5-(hydroxymethyl)-3-iodooxolan-2-yl]-2,4-dioxopyrimidin-5-yl]prop-2-enoic acid Chemical compound I[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(C=CC(O)=O)=C1 MIGXLQAFFHEHNT-PNHWDRBUSA-N 0.000 description 1
- JOBAEIKRKPWOHX-PNHWDRBUSA-N 3-[1-[(2r,3s,4s,5r)-3-hydroxy-5-(hydroxymethyl)-4-iodooxolan-2-yl]-2,4-dioxopyrimidin-5-yl]prop-2-enoic acid Chemical compound O[C@@H]1[C@H](I)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(C=CC(O)=O)=C1 JOBAEIKRKPWOHX-PNHWDRBUSA-N 0.000 description 1
- BONJIDVJFLTCSE-UHFFFAOYSA-N 3-methoxyprop-2-enoyl chloride Chemical compound COC=CC(Cl)=O BONJIDVJFLTCSE-UHFFFAOYSA-N 0.000 description 1
- 125000005917 3-methylpentyl group Chemical group 0.000 description 1
- ZTMWHTXUTZWLRH-CVTKMRTPSA-N 4,5-diamino-1-[(2r,3r,5s)-3-hydroxy-5-(hydroxymethyl)oxolan-2-yl]pyrimidin-2-one Chemical compound O=C1N=C(N)C(N)=CN1[C@H]1[C@H](O)C[C@@H](CO)O1 ZTMWHTXUTZWLRH-CVTKMRTPSA-N 0.000 description 1
- OXRABKGVJHFILE-CVTKMRTPSA-N 4-(hydroxyamino)-1-[(2r,3r,5s)-3-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-5-iodopyrimidin-2-one Chemical compound O1[C@H](CO)C[C@@H](O)[C@@H]1N1C(=O)N=C(NO)C(I)=C1 OXRABKGVJHFILE-CVTKMRTPSA-N 0.000 description 1
- XZGHIRWIYGTNLY-LKEWCRSYSA-N 4-(hydroxyamino)-1-[(2r,3r,5s)-3-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-5-methylpyrimidin-2-one Chemical compound O=C1N=C(NO)C(C)=CN1[C@H]1[C@H](O)C[C@@H](CO)O1 XZGHIRWIYGTNLY-LKEWCRSYSA-N 0.000 description 1
- KLVGCOVWOOSFCU-ZKYQVNSYSA-N 4-(hydroxyamino)-1-[(2r,3r,5s)-3-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-5-phenylpyrimidin-2-one Chemical compound O1[C@H](CO)C[C@@H](O)[C@@H]1N1C(=O)N=C(NO)C(C=2C=CC=CC=2)=C1 KLVGCOVWOOSFCU-ZKYQVNSYSA-N 0.000 description 1
- DBPIUBGCXGYPRT-RRKCRQDMSA-N 4-(hydroxyamino)-1-[(2r,4s,5r)-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-5-iodopyrimidin-2-one Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)N=C(NO)C(I)=C1 DBPIUBGCXGYPRT-RRKCRQDMSA-N 0.000 description 1
- ZLOIGESWDJYCTF-UHFFFAOYSA-N 4-Thiouridine Natural products OC1C(O)C(CO)OC1N1C(=O)NC(=S)C=C1 ZLOIGESWDJYCTF-UHFFFAOYSA-N 0.000 description 1
- HDFXQQWWLJAMPC-UMMCILCDSA-N 4-[(2r,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-2h-triazolo[4,5-d]pyrimidine-5,7-dione Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C2=C1N=NN2 HDFXQQWWLJAMPC-UMMCILCDSA-N 0.000 description 1
- TWBODIMIVBGBAE-UHFFFAOYSA-N 4-[bis(trimethylsilyl)amino]-5-fluoro-6-trimethylsilyl-1h-pyrimidin-2-one Chemical compound C[Si](C)(C)N([Si](C)(C)C)C1=NC(=O)NC([Si](C)(C)C)=C1F TWBODIMIVBGBAE-UHFFFAOYSA-N 0.000 description 1
- VGPGJAZBMZPSIH-UHFFFAOYSA-N 4-acetyl-4-amino-5-(2-bromoethenyl)-1,3-dihydropyrimidin-2-one Chemical compound C(C)(=O)C1(NC(NC=C1C=CBr)=O)N VGPGJAZBMZPSIH-UHFFFAOYSA-N 0.000 description 1
- AGXDKDCAOCASCV-UHFFFAOYSA-N 4-acetyl-4-amino-5-(2-chloroethenyl)-1,3-dihydropyrimidin-2-one Chemical compound C(C)(=O)C1(NC(NC=C1C=CCl)=O)N AGXDKDCAOCASCV-UHFFFAOYSA-N 0.000 description 1
- PSTRTTMVMXXABI-UHFFFAOYSA-N 4-acetyl-4-amino-5-(2-iodoethenyl)-1,3-dihydropyrimidin-2-one Chemical compound C(C)(=O)C1(NC(NC=C1C=CI)=O)N PSTRTTMVMXXABI-UHFFFAOYSA-N 0.000 description 1
- WDIWRKHHVVWUBP-UHFFFAOYSA-N 4-acetyl-4-amino-5-benzyl-1,3-dihydropyrimidin-2-one Chemical compound C(C)(=O)C1(NC(NC=C1CC1=CC=CC=C1)=O)N WDIWRKHHVVWUBP-UHFFFAOYSA-N 0.000 description 1
- GLCQKAWBGPGMMX-UHFFFAOYSA-N 4-acetyl-4-amino-5-bromo-1,3-dihydropyrimidin-2-one Chemical compound C(C)(=O)C1(NC(NC=C1Br)=O)N GLCQKAWBGPGMMX-UHFFFAOYSA-N 0.000 description 1
- GTHMWRSNHCOQQJ-UHFFFAOYSA-N 4-acetyl-4-amino-5-ethenyl-1,3-dihydropyrimidin-2-one Chemical compound C(C)(=O)C1(NC(NC=C1C=C)=O)N GTHMWRSNHCOQQJ-UHFFFAOYSA-N 0.000 description 1
- HWAIKOBJETVHMZ-UHFFFAOYSA-N 4-acetyl-4-amino-5-ethyl-1,3-dihydropyrimidin-2-one Chemical compound C(C)(=O)C1(NC(NC=C1CC)=O)N HWAIKOBJETVHMZ-UHFFFAOYSA-N 0.000 description 1
- MDYLPIQBOYSRRD-UHFFFAOYSA-N 4-acetyl-4-amino-5-iodo-1,3-dihydropyrimidin-2-one Chemical compound C(C)(=O)C1(NC(NC=C1I)=O)N MDYLPIQBOYSRRD-UHFFFAOYSA-N 0.000 description 1
- VXTVIWVATOLJBI-UHFFFAOYSA-N 4-acetyl-4-amino-5-methyl-1,3-dihydropyrimidin-2-one Chemical compound C(C)(=O)C1(NC(NC=C1C)=O)N VXTVIWVATOLJBI-UHFFFAOYSA-N 0.000 description 1
- UEBBTVMYBGACBZ-UHFFFAOYSA-N 4-acetyl-4-amino-5-phenyl-1,3-dihydropyrimidin-2-one Chemical compound C(C)(=O)C1(NC(NC=C1C1=CC=CC=C1)=O)N UEBBTVMYBGACBZ-UHFFFAOYSA-N 0.000 description 1
- BCZUPRDAAVVBSO-MJXNYTJMSA-N 4-acetylcytidine Chemical compound C1=CC(C(=O)C)(N)NC(=O)N1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 BCZUPRDAAVVBSO-MJXNYTJMSA-N 0.000 description 1
- UHDGCWIWMRVCDJ-PXBUCIJWSA-N 4-amino-1-[(2r,3r,4r,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]pyrimidin-2-one Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@H](O)[C@@H](O)[C@@H](CO)O1 UHDGCWIWMRVCDJ-PXBUCIJWSA-N 0.000 description 1
- HSQDGPFZYIOIAS-LKEWCRSYSA-N 4-amino-1-[(2r,3r,5s)-3-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-5-methylpyrimidin-2-one Chemical compound O=C1N=C(N)C(C)=CN1[C@H]1[C@H](O)C[C@@H](CO)O1 HSQDGPFZYIOIAS-LKEWCRSYSA-N 0.000 description 1
- OMLUXXHGDNOZLO-CVTKMRTPSA-N 4-amino-1-[(2r,3r,5s)-3-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-5-nitropyrimidin-2-one Chemical compound C1=C([N+]([O-])=O)C(N)=NC(=O)N1[C@H]1[C@H](O)C[C@@H](CO)O1 OMLUXXHGDNOZLO-CVTKMRTPSA-N 0.000 description 1
- JNJOKYZDFPLDTI-ZKYQVNSYSA-N 4-amino-1-[(2r,3r,5s)-3-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-5-phenylpyrimidin-2-one Chemical compound NC1=NC(=O)N([C@H]2[C@@H](C[C@@H](CO)O2)O)C=C1C1=CC=CC=C1 JNJOKYZDFPLDTI-ZKYQVNSYSA-N 0.000 description 1
- GRQRXJBZLAPNLF-GFQSEFKGSA-N 4-amino-1-[(2r,3s,4r,5r)-4-bromo-3-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-5-phenylpyrimidin-2-one Chemical compound NC1=NC(=O)N([C@H]2[C@@H]([C@@H](Br)[C@@H](CO)O2)O)C=C1C1=CC=CC=C1 GRQRXJBZLAPNLF-GFQSEFKGSA-N 0.000 description 1
- DYYBMHXBBJBAJV-UHFFFAOYSA-N 4-amino-4-benzoyl-5-(2-bromoethenyl)-1,3-dihydropyrimidin-2-one Chemical compound C(C1=CC=CC=C1)(=O)C1(NC(NC=C1C=CBr)=O)N DYYBMHXBBJBAJV-UHFFFAOYSA-N 0.000 description 1
- XHHGWMCVLNNJFD-UHFFFAOYSA-N 4-amino-4-benzoyl-5-(2-chloroethenyl)-1,3-dihydropyrimidin-2-one Chemical compound C(C1=CC=CC=C1)(=O)C1(NC(NC=C1C=CCl)=O)N XHHGWMCVLNNJFD-UHFFFAOYSA-N 0.000 description 1
- USFZSOBWSJBLSG-UHFFFAOYSA-N 4-amino-4-benzoyl-5-(2-iodoethenyl)-1,3-dihydropyrimidin-2-one Chemical compound C(C1=CC=CC=C1)(=O)C1(NC(NC=C1C=CI)=O)N USFZSOBWSJBLSG-UHFFFAOYSA-N 0.000 description 1
- ADUXXOSUORQSHN-UHFFFAOYSA-N 4-amino-4-benzoyl-5-ethenyl-1,3-dihydropyrimidin-2-one Chemical compound C(C1=CC=CC=C1)(=O)C1(NC(NC=C1C=C)=O)N ADUXXOSUORQSHN-UHFFFAOYSA-N 0.000 description 1
- YFFMCRGRRYQJNR-UHFFFAOYSA-N 4-amino-4-benzoyl-5-fluoro-1,3-dihydropyrimidin-2-one Chemical compound C=1C=CC=CC=1C(=O)C1(N)NC(=O)NC=C1F YFFMCRGRRYQJNR-UHFFFAOYSA-N 0.000 description 1
- XLCNQDFKITWFBH-UHFFFAOYSA-N 4-amino-4-benzoyl-5-phenyl-1,3-dihydropyrimidin-2-one Chemical compound C(C1=CC=CC=C1)(=O)C1(NC(NC=C1C1=CC=CC=C1)=O)N XLCNQDFKITWFBH-UHFFFAOYSA-N 0.000 description 1
- ASODOEFCCLXZJC-QVHKTLOISA-N 4-amino-5-benzyl-1-[(2r,3r,4r,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]pyrimidin-2-one Chemical compound NC1=NC(=O)N([C@H]2[C@@H]([C@@H](O)[C@@H](CO)O2)O)C=C1CC1=CC=CC=C1 ASODOEFCCLXZJC-QVHKTLOISA-N 0.000 description 1
- QSTQYDJYMNXVLA-GZBFAFLISA-N 4-amino-5-benzyl-1-[(2r,3r,5s)-3-hydroxy-5-(hydroxymethyl)oxolan-2-yl]pyrimidin-2-one Chemical compound NC1=NC(=O)N([C@H]2[C@@H](C[C@@H](CO)O2)O)C=C1CC1=CC=CC=C1 QSTQYDJYMNXVLA-GZBFAFLISA-N 0.000 description 1
- VNBNEWDWZPEQSU-QXFUBDJGSA-N 4-amino-5-ethyl-1-[(2r,3r,5s)-3-hydroxy-5-(hydroxymethyl)oxolan-2-yl]pyrimidin-2-one Chemical compound O=C1N=C(N)C(CC)=CN1[C@H]1[C@H](O)C[C@@H](CO)O1 VNBNEWDWZPEQSU-QXFUBDJGSA-N 0.000 description 1
- FARVDDXVBHNRIX-CVTKMRTPSA-N 4-amino-5-fluoro-1-[(2r,3r,5s)-3-hydroxy-5-(hydroxymethyl)oxolan-2-yl]pyrimidin-2-one Chemical compound C1=C(F)C(N)=NC(=O)N1[C@H]1[C@H](O)C[C@@H](CO)O1 FARVDDXVBHNRIX-CVTKMRTPSA-N 0.000 description 1
- KKNLRVCDDWPTEX-LKEWCRSYSA-N 4-amino-6-(chloromethyl)-1-[(2r,3r,5s)-3-hydroxy-5-(hydroxymethyl)oxolan-2-yl]pyrimidin-2-one Chemical compound O=C1N=C(N)C=C(CCl)N1[C@H]1[C@H](O)C[C@@H](CO)O1 KKNLRVCDDWPTEX-LKEWCRSYSA-N 0.000 description 1
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 description 1
- ZUTJNUARHXDQTO-UHFFFAOYSA-N 4-methoxy-N-(2-oxo-5-phenyl-1H-pyrimidin-6-yl)benzamide Chemical compound COc1ccc(cc1)C(=O)Nc1nc(=O)[nH]cc1-c1ccccc1 ZUTJNUARHXDQTO-UHFFFAOYSA-N 0.000 description 1
- NIPKRLLKGZROTE-UHFFFAOYSA-N 4-methoxy-n-(2-oxo-1h-pyrimidin-6-yl)benzamide Chemical compound C1=CC(OC)=CC=C1C(=O)NC1=NC(=O)NC=C1 NIPKRLLKGZROTE-UHFFFAOYSA-N 0.000 description 1
- MHXRFVLFXVBCOB-UHFFFAOYSA-N 4-methoxy-n-(5-methyl-2-oxo-1h-pyrimidin-6-yl)benzamide Chemical compound C1=CC(OC)=CC=C1C(=O)NC1=C(C)C=NC(=O)N1 MHXRFVLFXVBCOB-UHFFFAOYSA-N 0.000 description 1
- 125000000590 4-methylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 description 1
- ZLOIGESWDJYCTF-XVFCMESISA-N 4-thiouridine Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=S)C=C1 ZLOIGESWDJYCTF-XVFCMESISA-N 0.000 description 1
- PJUHJSYJNXQIEB-FDDDBJFASA-N 5-(2-bromoethenyl)-1-[(2r,3r,4r,5r)-4-hydroxy-5-(hydroxymethyl)-3-iodooxolan-2-yl]pyrimidine-2,4-dione Chemical compound I[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(C=CBr)=C1 PJUHJSYJNXQIEB-FDDDBJFASA-N 0.000 description 1
- OULNWJACTLGKRX-FDDDBJFASA-N 5-(2-bromoethenyl)-1-[(2r,3s,4s,5r)-3-hydroxy-5-(hydroxymethyl)-4-iodooxolan-2-yl]pyrimidine-2,4-dione Chemical compound O[C@@H]1[C@H](I)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(C=CBr)=C1 OULNWJACTLGKRX-FDDDBJFASA-N 0.000 description 1
- BLXGZIDBSXVMLU-UHFFFAOYSA-N 5-(2-bromoethenyl)-1h-pyrimidine-2,4-dione Chemical compound BrC=CC1=CNC(=O)NC1=O BLXGZIDBSXVMLU-UHFFFAOYSA-N 0.000 description 1
- TYNILJZZNBHCFZ-UHFFFAOYSA-N 5-(2-bromoethenyl)-6-(hydroxyamino)-1H-pyrimidin-2-one Chemical compound BrC=CC=1C(=NC(NC=1)=O)NO TYNILJZZNBHCFZ-UHFFFAOYSA-N 0.000 description 1
- OVYDCOHNRQJCCI-FDDDBJFASA-N 5-(2-chloroethenyl)-1-[(2r,3r,4r,5r)-4-hydroxy-5-(hydroxymethyl)-3-iodooxolan-2-yl]pyrimidine-2,4-dione Chemical compound I[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(C=CCl)=C1 OVYDCOHNRQJCCI-FDDDBJFASA-N 0.000 description 1
- FCNOVXBXRDBVDU-FDDDBJFASA-N 5-(2-chloroethenyl)-1-[(2r,3s,4s,5r)-3-hydroxy-5-(hydroxymethyl)-4-iodooxolan-2-yl]pyrimidine-2,4-dione Chemical compound O[C@@H]1[C@H](I)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(C=CCl)=C1 FCNOVXBXRDBVDU-FDDDBJFASA-N 0.000 description 1
- HXKGHWDYRHTTKC-DJLDLDEBSA-N 5-(2-chloroethenyl)-4-(hydroxyamino)-1-[(2R,4S,5R)-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]pyrimidin-2-one Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)N=C(NO)C(C=CCl)=C1 HXKGHWDYRHTTKC-DJLDLDEBSA-N 0.000 description 1
- UCDUBKRXOPMNGH-UHFFFAOYSA-N 5-(chloromethyl)-1h-pyrimidine-2,4-dione Chemical class ClCC1=CNC(=O)NC1=O UCDUBKRXOPMNGH-UHFFFAOYSA-N 0.000 description 1
- PIRFCSWHKKSMFQ-IQJOONFLSA-N 5-(ethoxymethyl)-1-[(2r,3r,5s)-3-hydroxy-5-(hydroxymethyl)oxolan-2-yl]pyrimidine-2,4-dione Chemical compound O=C1NC(=O)C(COCC)=CN1[C@H]1[C@H](O)C[C@@H](CO)O1 PIRFCSWHKKSMFQ-IQJOONFLSA-N 0.000 description 1
- IPNJUDGMIKAVPT-UHFFFAOYSA-N 5-[[1,3-dihydroxy-2-(hydroxymethyl)propan-2-yl]iminomethyl]-6-hydroxy-1H-pyrimidine-2,4-dione Chemical compound C(C(CO)(CO)N=CC1=C(NC(=O)NC1=O)O)O IPNJUDGMIKAVPT-UHFFFAOYSA-N 0.000 description 1
- PVQJTEJDDJDNDF-SKWCMTHISA-N 5-acetyl-1-[(2r,3r,5s)-3-hydroxy-5-(hydroxymethyl)oxolan-2-yl]pyrimidine-2,4-dione Chemical compound O=C1NC(=O)C(C(=O)C)=CN1[C@H]1[C@H](O)C[C@@H](CO)O1 PVQJTEJDDJDNDF-SKWCMTHISA-N 0.000 description 1
- XMBXVJFERXYPSR-UHFFFAOYSA-N 5-acetyl-6-(hydroxyamino)-1H-pyrimidin-2-one Chemical compound C(C)(=O)C=1C(=NC(NC=1)=O)NO XMBXVJFERXYPSR-UHFFFAOYSA-N 0.000 description 1
- YBTWWWIJBCCYNR-UAKXSSHOSA-N 5-amino-1-[(2r,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]pyrimidine-2,4-dione Chemical compound O=C1NC(=O)C(N)=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 YBTWWWIJBCCYNR-UAKXSSHOSA-N 0.000 description 1
- KEAZEXPUHVYBQL-RGCMKSIDSA-N 5-benzyl-1-[(2r,3r,4r,5r)-4-hydroxy-5-(hydroxymethyl)-3-iodooxolan-2-yl]pyrimidine-2,4-dione Chemical compound I[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(CC=2C=CC=CC=2)=C1 KEAZEXPUHVYBQL-RGCMKSIDSA-N 0.000 description 1
- QTZGIBORRONLGN-RGCMKSIDSA-N 5-benzyl-1-[(2r,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-4-(hydroxyamino)pyrimidin-2-one Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)N=C(NO)C(CC=2C=CC=CC=2)=C1 QTZGIBORRONLGN-RGCMKSIDSA-N 0.000 description 1
- RXIHRXSUCNUZFD-RGCMKSIDSA-N 5-benzyl-1-[(2r,3s,4s,5r)-3-hydroxy-5-(hydroxymethyl)-4-iodooxolan-2-yl]pyrimidine-2,4-dione Chemical compound O[C@@H]1[C@H](I)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(CC=2C=CC=CC=2)=C1 RXIHRXSUCNUZFD-RGCMKSIDSA-N 0.000 description 1
- RPZOVLGFKOOIRP-UHFFFAOYSA-N 5-benzyl-1h-pyrimidine-2,4-dione Chemical compound O=C1NC(=O)NC=C1CC1=CC=CC=C1 RPZOVLGFKOOIRP-UHFFFAOYSA-N 0.000 description 1
- FZYQSFANDZVZBS-GZBFAFLISA-N 5-benzyl-4-(hydroxyamino)-1-[(2r,3r,5s)-3-hydroxy-5-(hydroxymethyl)oxolan-2-yl]pyrimidin-2-one Chemical compound O1[C@H](CO)C[C@@H](O)[C@@H]1N1C(=O)N=C(NO)C(CC=2C=CC=CC=2)=C1 FZYQSFANDZVZBS-GZBFAFLISA-N 0.000 description 1
- SNHLLWFRSHBIBA-UAKXSSHOSA-N 5-bromo-1-[(2r,3r,4r,5r)-4-hydroxy-5-(hydroxymethyl)-3-iodooxolan-2-yl]pyrimidine-2,4-dione Chemical compound I[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(Br)=C1 SNHLLWFRSHBIBA-UAKXSSHOSA-N 0.000 description 1
- SQIFTTCATAHMLW-CVTKMRTPSA-N 5-bromo-1-[(2r,3r,5s)-3-hydroxy-5-(hydroxymethyl)oxolan-2-yl]pyrimidine-2,4-dione Chemical compound O1[C@H](CO)C[C@@H](O)[C@@H]1N1C(=O)NC(=O)C(Br)=C1 SQIFTTCATAHMLW-CVTKMRTPSA-N 0.000 description 1
- JLXDQFOOVSOMMQ-UAKXSSHOSA-N 5-bromo-1-[(2r,3s,4s,5r)-3-hydroxy-5-(hydroxymethyl)-4-iodooxolan-2-yl]pyrimidine-2,4-dione Chemical compound O[C@@H]1[C@H](I)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(Br)=C1 JLXDQFOOVSOMMQ-UAKXSSHOSA-N 0.000 description 1
- KSWWAMHEHUOXHS-CVTKMRTPSA-N 5-bromo-4-(hydroxyamino)-1-[(2r,3r,5s)-3-hydroxy-5-(hydroxymethyl)oxolan-2-yl]pyrimidin-2-one Chemical compound O1[C@H](CO)C[C@@H](O)[C@@H]1N1C(=O)N=C(NO)C(Br)=C1 KSWWAMHEHUOXHS-CVTKMRTPSA-N 0.000 description 1
- KCOGFNTXEAOZLZ-RRKCRQDMSA-N 5-bromo-4-(hydroxyamino)-1-[(2r,4s,5r)-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]pyrimidin-2-one Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)N=C(NO)C(Br)=C1 KCOGFNTXEAOZLZ-RRKCRQDMSA-N 0.000 description 1
- LQLQRFGHAALLLE-UHFFFAOYSA-N 5-bromouracil Chemical compound BrC1=CNC(=O)NC1=O LQLQRFGHAALLLE-UHFFFAOYSA-N 0.000 description 1
- BTHWTPDYKXULHF-UAKXSSHOSA-N 5-chloro-1-[(2r,3r,4r,5r)-4-hydroxy-5-(hydroxymethyl)-3-iodooxolan-2-yl]pyrimidine-2,4-dione Chemical compound I[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(Cl)=C1 BTHWTPDYKXULHF-UAKXSSHOSA-N 0.000 description 1
- UDEHQVGEOQSGAC-UAKXSSHOSA-N 5-chloro-1-[(2r,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-4-(hydroxyamino)pyrimidin-2-one Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)N=C(NO)C(Cl)=C1 UDEHQVGEOQSGAC-UAKXSSHOSA-N 0.000 description 1
- LDCUBKKZHSYQTJ-UAKXSSHOSA-N 5-chloro-1-[(2r,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]pyrimidine-2,4-dione Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(Cl)=C1 LDCUBKKZHSYQTJ-UAKXSSHOSA-N 0.000 description 1
- ILMMERUZZBNMBN-UAKXSSHOSA-N 5-chloro-1-[(2r,3s,4s,5r)-3-hydroxy-5-(hydroxymethyl)-4-iodooxolan-2-yl]pyrimidine-2,4-dione Chemical compound O[C@@H]1[C@H](I)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(Cl)=C1 ILMMERUZZBNMBN-UAKXSSHOSA-N 0.000 description 1
- CVICEEPAFUYBJG-UHFFFAOYSA-N 5-chloro-2,2-difluoro-1,3-benzodioxole Chemical group C1=C(Cl)C=C2OC(F)(F)OC2=C1 CVICEEPAFUYBJG-UHFFFAOYSA-N 0.000 description 1
- RNFMGIYVJJFDEK-CVTKMRTPSA-N 5-chloro-4-(hydroxyamino)-1-[(2r,3r,5s)-3-hydroxy-5-(hydroxymethyl)oxolan-2-yl]pyrimidin-2-one Chemical compound O1[C@H](CO)C[C@@H](O)[C@@H]1N1C(=O)N=C(NO)C(Cl)=C1 RNFMGIYVJJFDEK-CVTKMRTPSA-N 0.000 description 1
- PDRJSODMGJZJEF-RRKCRQDMSA-N 5-chloro-4-(hydroxyamino)-1-[(2r,4s,5r)-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]pyrimidin-2-one Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)N=C(NO)C(Cl)=C1 PDRJSODMGJZJEF-RRKCRQDMSA-N 0.000 description 1
- RTNMWMJSFSIKFY-CVTKMRTPSA-N 5-diazo-1-[(2R,3R,5S)-3-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-1,3-diazinane-2,4-dione Chemical compound OC[C@@H]1C[C@@H](O)[C@@H](O1)N1CC(=[N+]=[N-])C(=O)NC1=O RTNMWMJSFSIKFY-CVTKMRTPSA-N 0.000 description 1
- STMVNFFOTMHLOY-FDDDBJFASA-N 5-ethenyl-1-[(2r,3r,4r,5r)-4-hydroxy-5-(hydroxymethyl)-3-iodooxolan-2-yl]pyrimidine-2,4-dione Chemical compound I[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(C=C)=C1 STMVNFFOTMHLOY-FDDDBJFASA-N 0.000 description 1
- PBNDZFUMWJSLKA-FDDDBJFASA-N 5-ethenyl-1-[(2r,3s,4s,5r)-3-hydroxy-5-(hydroxymethyl)-4-iodooxolan-2-yl]pyrimidine-2,4-dione Chemical compound O[C@@H]1[C@H](I)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(C=C)=C1 PBNDZFUMWJSLKA-FDDDBJFASA-N 0.000 description 1
- ZRYZBEQILKESAW-UHFFFAOYSA-N 5-ethenyl-1h-pyrimidine-2,4-dione Chemical class C=CC1=CNC(=O)NC1=O ZRYZBEQILKESAW-UHFFFAOYSA-N 0.000 description 1
- DVHMLELCEKXWQZ-DJLDLDEBSA-N 5-ethenyl-4-(hydroxyamino)-1-[(2r,4s,5r)-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]pyrimidin-2-one Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)N=C(NO)C(C=C)=C1 DVHMLELCEKXWQZ-DJLDLDEBSA-N 0.000 description 1
- PYNRRDAWSPJJPO-FDDDBJFASA-N 5-ethyl-1-[(2r,3r,4r,5r)-4-hydroxy-5-(hydroxymethyl)-3-iodooxolan-2-yl]pyrimidine-2,4-dione Chemical compound O=C1NC(=O)C(CC)=CN1[C@H]1[C@H](I)[C@H](O)[C@@H](CO)O1 PYNRRDAWSPJJPO-FDDDBJFASA-N 0.000 description 1
- BCYWVIKBRHSUEW-FDDDBJFASA-N 5-ethyl-1-[(2r,3s,4s,5r)-3-hydroxy-5-(hydroxymethyl)-4-iodooxolan-2-yl]pyrimidine-2,4-dione Chemical compound O=C1NC(=O)C(CC)=CN1[C@H]1[C@H](O)[C@H](I)[C@@H](CO)O1 BCYWVIKBRHSUEW-FDDDBJFASA-N 0.000 description 1
- VTJDRHFZWZITQR-QXFUBDJGSA-N 5-ethyl-4-(hydroxyamino)-1-[(2r,3r,5s)-3-hydroxy-5-(hydroxymethyl)oxolan-2-yl]pyrimidin-2-one Chemical compound O=C1N=C(NO)C(CC)=CN1[C@H]1[C@H](O)C[C@@H](CO)O1 VTJDRHFZWZITQR-QXFUBDJGSA-N 0.000 description 1
- JRIUTKGLGFWMIB-DJLDLDEBSA-N 5-ethyl-4-(hydroxyamino)-1-[(2r,4s,5r)-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]pyrimidin-2-one Chemical compound O=C1N=C(NO)C(CC)=CN1[C@@H]1O[C@H](CO)[C@@H](O)C1 JRIUTKGLGFWMIB-DJLDLDEBSA-N 0.000 description 1
- VCQODJHGXOWMKY-UHFFFAOYSA-N 5-ethyl-6-(hydroxyamino)-1H-pyrimidin-2-one Chemical compound ONC1=NC(NC=C1CC)=O VCQODJHGXOWMKY-UHFFFAOYSA-N 0.000 description 1
- MJTSPTRANGPNRJ-UHFFFAOYSA-N 5-ethylpyrimidine Chemical compound CCC1=CN=CN=C1 MJTSPTRANGPNRJ-UHFFFAOYSA-N 0.000 description 1
- DZWHQCFOHTUASD-FDDDBJFASA-N 5-ethynyl-1-[(2r,3r,4r,5r)-4-hydroxy-5-(hydroxymethyl)-3-iodooxolan-2-yl]pyrimidine-2,4-dione Chemical compound I[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(C#C)=C1 DZWHQCFOHTUASD-FDDDBJFASA-N 0.000 description 1
- DYHBWMODWFBHNR-QXFUBDJGSA-N 5-ethynyl-1-[(2r,3r,5s)-3-hydroxy-5-(hydroxymethyl)oxolan-2-yl]pyrimidine-2,4-dione Chemical compound O1[C@H](CO)C[C@@H](O)[C@@H]1N1C(=O)NC(=O)C(C#C)=C1 DYHBWMODWFBHNR-QXFUBDJGSA-N 0.000 description 1
- JQBCSZBLDMRGAT-FDDDBJFASA-N 5-ethynyl-1-[(2r,3s,4s,5r)-3-hydroxy-5-(hydroxymethyl)-4-iodooxolan-2-yl]pyrimidine-2,4-dione Chemical compound O[C@@H]1[C@H](I)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(C#C)=C1 JQBCSZBLDMRGAT-FDDDBJFASA-N 0.000 description 1
- VEWNBFGPXIWYIJ-QXFUBDJGSA-N 5-ethynyl-4-(hydroxyamino)-1-[(2r,3r,5s)-3-hydroxy-5-(hydroxymethyl)oxolan-2-yl]pyrimidin-2-one Chemical compound O1[C@H](CO)C[C@@H](O)[C@@H]1N1C(=O)N=C(NO)C(C#C)=C1 VEWNBFGPXIWYIJ-QXFUBDJGSA-N 0.000 description 1
- YMSQUIZJKFDILI-UAKXSSHOSA-N 5-fluoro-1-[(2r,3r,4r,5r)-4-hydroxy-5-(hydroxymethyl)-3-iodooxolan-2-yl]pyrimidine-2,4-dione Chemical compound I[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(F)=C1 YMSQUIZJKFDILI-UAKXSSHOSA-N 0.000 description 1
- NWMLDZGYLDNAOU-UAKXSSHOSA-N 5-fluoro-1-[(2r,3s,4s,5r)-3-hydroxy-5-(hydroxymethyl)-4-iodooxolan-2-yl]pyrimidine-2,4-dione Chemical compound O[C@@H]1[C@H](I)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(F)=C1 NWMLDZGYLDNAOU-UAKXSSHOSA-N 0.000 description 1
- KTOBOVBMLZSTBB-CVTKMRTPSA-N 5-fluoro-4-(hydroxyamino)-1-[(2r,3r,5s)-3-hydroxy-5-(hydroxymethyl)oxolan-2-yl]pyrimidin-2-one Chemical compound O1[C@H](CO)C[C@@H](O)[C@@H]1N1C(=O)N=C(NO)C(F)=C1 KTOBOVBMLZSTBB-CVTKMRTPSA-N 0.000 description 1
- LNPTVJYGBNLLGQ-RRKCRQDMSA-N 5-fluoro-4-(hydroxyamino)-1-[(2r,4s,5r)-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]pyrimidin-2-one Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)N=C(NO)C(F)=C1 LNPTVJYGBNLLGQ-RRKCRQDMSA-N 0.000 description 1
- FHIDNBAQOFJWCA-UAKXSSHOSA-N 5-fluorouridine Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(F)=C1 FHIDNBAQOFJWCA-UAKXSSHOSA-N 0.000 description 1
- LRSASMSXMSNRBT-UHFFFAOYSA-N 5-methylcytosine Chemical compound CC1=CNC(=O)N=C1N LRSASMSXMSNRBT-UHFFFAOYSA-N 0.000 description 1
- NOYDQGFVFOQSAJ-UHFFFAOYSA-N 5-nitropyrimidine Chemical compound [O-][N+](=O)C1=CN=CN=C1 NOYDQGFVFOQSAJ-UHFFFAOYSA-N 0.000 description 1
- UIKIQOAXFYAWPW-UHFFFAOYSA-N 5-phenyl-1h-pyrimidine-2,4-dione Chemical compound O=C1NC(=O)NC=C1C1=CC=CC=C1 UIKIQOAXFYAWPW-UHFFFAOYSA-N 0.000 description 1
- VOBFOFTXJVSVTJ-UHFFFAOYSA-N 5-prop-2-enyl-1h-pyrimidine-2,4-dione Chemical compound C=CCC1=CNC(=O)NC1=O VOBFOFTXJVSVTJ-UHFFFAOYSA-N 0.000 description 1
- FUJGTGXXJJMRRY-LKEWCRSYSA-N 6-(aminomethyl)-1-[(2r,3r,5s)-3-hydroxy-5-(hydroxymethyl)oxolan-2-yl]pyrimidine-2,4-dione Chemical compound NCC1=CC(=O)NC(=O)N1[C@H]1[C@H](O)C[C@@H](CO)O1 FUJGTGXXJJMRRY-LKEWCRSYSA-N 0.000 description 1
- OSHIQPFXKULOPB-UHFFFAOYSA-N 6-(hydroxyamino)-1h-pyrimidin-2-one Chemical compound ONC1=CC=NC(=O)N1 OSHIQPFXKULOPB-UHFFFAOYSA-N 0.000 description 1
- OWMWDJCDWONHJY-UHFFFAOYSA-N 6-(hydroxyamino)-2-oxo-1H-pyrimidine-5-carboxamide Chemical compound NC(=O)C=1C(=NC(NC=1)=O)NO OWMWDJCDWONHJY-UHFFFAOYSA-N 0.000 description 1
- HTZVXIGQQLRNDX-UHFFFAOYSA-N 6-(hydroxyamino)-5-(2-iodoethenyl)-1H-pyrimidin-2-one Chemical compound IC=CC=1C(=NC(NC=1)=O)NO HTZVXIGQQLRNDX-UHFFFAOYSA-N 0.000 description 1
- COVJFYMYPVAZHM-UHFFFAOYSA-N 6-(hydroxyamino)-5-propyl-1H-pyrimidin-2-one Chemical compound C(CC)C=1C(=NC(NC=1)=O)NO COVJFYMYPVAZHM-UHFFFAOYSA-N 0.000 description 1
- KFDKBQHGALFUAJ-UHFFFAOYSA-N 6-amino-2-oxo-1h-pyrimidine-5-carbonitrile Chemical compound NC=1NC(=O)N=CC=1C#N KFDKBQHGALFUAJ-UHFFFAOYSA-N 0.000 description 1
- IADBQAOIOMKMLD-YHQHWJDSSA-N 6-amino-3-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-6-hydroxy-1H-pyrimidin-2-one Chemical compound C1=CC(N)(O)NC(=O)N1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 IADBQAOIOMKMLD-YHQHWJDSSA-N 0.000 description 1
- QFVKLKDEXOWFSL-UHFFFAOYSA-N 6-amino-5-bromo-1h-pyrimidin-2-one Chemical compound NC=1NC(=O)N=CC=1Br QFVKLKDEXOWFSL-UHFFFAOYSA-N 0.000 description 1
- WPIODDDSOONWLM-UHFFFAOYSA-N 6-amino-5-ethenyl-1h-pyrimidin-2-one Chemical compound NC1=NC(=O)NC=C1C=C WPIODDDSOONWLM-UHFFFAOYSA-N 0.000 description 1
- CZJGCEGNCSGRBI-UHFFFAOYSA-N 6-amino-5-ethyl-1h-pyrimidin-2-one Chemical compound CCC1=CNC(=O)N=C1N CZJGCEGNCSGRBI-UHFFFAOYSA-N 0.000 description 1
- PPYAFPNEHGRGIQ-UHFFFAOYSA-N 6-amino-5-ethynyl-1h-pyrimidin-2-one Chemical compound NC1=NC(=O)NC=C1C#C PPYAFPNEHGRGIQ-UHFFFAOYSA-N 0.000 description 1
- UFVWJVAMULFOMC-UHFFFAOYSA-N 6-amino-5-iodo-1h-pyrimidin-2-one Chemical compound NC=1NC(=O)N=CC=1I UFVWJVAMULFOMC-UHFFFAOYSA-N 0.000 description 1
- BCOXKGKOSQVPKS-JVLSTEMRSA-N 6-benzoyl-1-[(2r,3r,5s)-3-hydroxy-5-(hydroxymethyl)oxolan-2-yl]pyrimidine-2,4-dione Chemical compound O1[C@H](CO)C[C@@H](O)[C@@H]1N1C(=O)NC(=O)C=C1C(=O)C1=CC=CC=C1 BCOXKGKOSQVPKS-JVLSTEMRSA-N 0.000 description 1
- RYYIULNRIVUMTQ-UHFFFAOYSA-N 6-chloroguanine Chemical compound NC1=NC(Cl)=C2N=CNC2=N1 RYYIULNRIVUMTQ-UHFFFAOYSA-N 0.000 description 1
- NKGPJODWTZCHGF-KQYNXXCUSA-N 6-thioinosinic acid Chemical class O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C2=NC=NC(S)=C2N=C1 NKGPJODWTZCHGF-KQYNXXCUSA-N 0.000 description 1
- YYVYAPXYZVYDHN-UHFFFAOYSA-N 9,10-phenanthroquinone Chemical compound C1=CC=C2C(=O)C(=O)C3=CC=CC=C3C2=C1 YYVYAPXYZVYDHN-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 206010001052 Acute respiratory distress syndrome Diseases 0.000 description 1
- 241000178320 Alfuy virus Species 0.000 description 1
- OSDWBNJEKMUWAV-UHFFFAOYSA-N Allyl chloride Chemical compound ClCC=C OSDWBNJEKMUWAV-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- 208000000058 Anaplasia Diseases 0.000 description 1
- 241000272517 Anseriformes Species 0.000 description 1
- 241000271566 Aves Species 0.000 description 1
- 241000711404 Avian avulavirus 1 Species 0.000 description 1
- 206010004146 Basal cell carcinoma Diseases 0.000 description 1
- 208000027496 Behcet disease Diseases 0.000 description 1
- 208000009137 Behcet syndrome Diseases 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- 241000530623 Bovine viral diarrhea virus 2 Species 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- 206010006448 Bronchiolitis Diseases 0.000 description 1
- 239000002126 C01EB10 - Adenosine Substances 0.000 description 1
- DASVKUIZNBQCTB-DJLDLDEBSA-N C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)N=C(NO)C(C=CBr)=C1 Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)N=C(NO)C(C=CBr)=C1 DASVKUIZNBQCTB-DJLDLDEBSA-N 0.000 description 1
- KGNQWOKORPNQBA-DJLDLDEBSA-N C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)N=C(NO)C(C=CI)=C1 Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)N=C(NO)C(C=CI)=C1 KGNQWOKORPNQBA-DJLDLDEBSA-N 0.000 description 1
- UHNRLQRZRNKOKU-UHFFFAOYSA-N CCN(CC1=NC2=C(N1)C1=CC=C(C=C1N=C2N)C1=NNC=C1)C(C)=O Chemical compound CCN(CC1=NC2=C(N1)C1=CC=C(C=C1N=C2N)C1=NNC=C1)C(C)=O UHNRLQRZRNKOKU-UHFFFAOYSA-N 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- 229910004664 Cerium(III) chloride Inorganic materials 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 206010063209 Chronic allograft nephropathy Diseases 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- 108010035532 Collagen Proteins 0.000 description 1
- 102000008186 Collagen Human genes 0.000 description 1
- 208000035473 Communicable disease Diseases 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- 229910021595 Copper(I) iodide Inorganic materials 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- 125000000222 D-xylofuranosyl group Chemical group [H]OC([H])([H])[C@@]1([H])OC([H])(*)[C@]([H])(O[H])[C@@]1([H])O[H] 0.000 description 1
- SRBFZHDQGSBBOR-IOVATXLUSA-N D-xylopyranose Chemical compound O[C@@H]1COC(O)[C@H](O)[C@H]1O SRBFZHDQGSBBOR-IOVATXLUSA-N 0.000 description 1
- 208000001490 Dengue Diseases 0.000 description 1
- 206010012310 Dengue fever Diseases 0.000 description 1
- 241000710827 Dengue virus 1 Species 0.000 description 1
- 241000710815 Dengue virus 2 Species 0.000 description 1
- 241000710872 Dengue virus 3 Species 0.000 description 1
- 241000710844 Dengue virus 4 Species 0.000 description 1
- 241000710829 Dengue virus group Species 0.000 description 1
- 201000004624 Dermatitis Diseases 0.000 description 1
- 206010012438 Dermatitis atopic Diseases 0.000 description 1
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical group [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 241000712471 Dhori virus Species 0.000 description 1
- 208000007342 Diabetic Nephropathies Diseases 0.000 description 1
- BUDQDWGNQVEFAC-UHFFFAOYSA-N Dihydropyran Chemical compound C1COC=CC1 BUDQDWGNQVEFAC-UHFFFAOYSA-N 0.000 description 1
- 101710091045 Envelope protein Proteins 0.000 description 1
- 241000283086 Equidae Species 0.000 description 1
- 241000588775 Erythrops Species 0.000 description 1
- 206010016654 Fibrosis Diseases 0.000 description 1
- 230000005526 G1 to G0 transition Effects 0.000 description 1
- 206010018364 Glomerulonephritis Diseases 0.000 description 1
- 108060003393 Granulin Proteins 0.000 description 1
- 238000003747 Grignard reaction Methods 0.000 description 1
- 241000197304 H2N2 subtype Species 0.000 description 1
- 238000006546 Horner-Wadsworth-Emmons reaction Methods 0.000 description 1
- 241000725303 Human immunodeficiency virus Species 0.000 description 1
- 238000012404 In vitro experiment Methods 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 241000710842 Japanese encephalitis virus Species 0.000 description 1
- 241000178324 Koutango virus Species 0.000 description 1
- 241000710912 Kunjin virus Species 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 108091026898 Leader sequence (mRNA) Proteins 0.000 description 1
- 239000002841 Lewis acid Substances 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-L Malonate Chemical compound [O-]C(=O)CC([O-])=O OFOBLEOULBTSOW-UHFFFAOYSA-L 0.000 description 1
- 241001559185 Mammalian rubulavirus 5 Species 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 201000005505 Measles Diseases 0.000 description 1
- 241000712079 Measles morbillivirus Species 0.000 description 1
- 241001147428 Modoc virus group Species 0.000 description 1
- 241000712045 Morbillivirus Species 0.000 description 1
- 241000711386 Mumps virus Species 0.000 description 1
- 241000711408 Murine respirovirus Species 0.000 description 1
- 241000710908 Murray Valley encephalitis virus Species 0.000 description 1
- NIDVTARKFBZMOT-PEBGCTIMSA-N N(4)-acetylcytidine Chemical compound O=C1N=C(NC(=O)C)C=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 NIDVTARKFBZMOT-PEBGCTIMSA-N 0.000 description 1
- ZSXGLVDWWRXATF-UHFFFAOYSA-N N,N-dimethylformamide dimethyl acetal Chemical compound COC(OC)N(C)C ZSXGLVDWWRXATF-UHFFFAOYSA-N 0.000 description 1
- LVDRREOUMKACNJ-BKMJKUGQSA-N N-[(2R,3S)-2-(4-chlorophenyl)-1-(1,4-dimethyl-2-oxoquinolin-7-yl)-6-oxopiperidin-3-yl]-2-methylpropane-1-sulfonamide Chemical compound CC(C)CS(=O)(=O)N[C@H]1CCC(=O)N([C@@H]1c1ccc(Cl)cc1)c1ccc2c(C)cc(=O)n(C)c2c1 LVDRREOUMKACNJ-BKMJKUGQSA-N 0.000 description 1
- BAXSTEDDPVUGBT-UHFFFAOYSA-N N-[5-(2-iodoethenyl)-2-oxo-1H-pyrimidin-6-yl]-4-methoxybenzamide Chemical compound C(C1=CC=C(C=C1)OC)(=O)NC1=NC(NC=C1C=CI)=O BAXSTEDDPVUGBT-UHFFFAOYSA-N 0.000 description 1
- 229930182507 Neplanocin Natural products 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 101800001019 Non-structural protein 4B Proteins 0.000 description 1
- 241001147430 Ntaya virus group Species 0.000 description 1
- 238000010934 O-alkylation reaction Methods 0.000 description 1
- ZAEILDGYYKZLQP-QXFUBDJGSA-N O1[C@H](CO)C[C@@H](O)[C@@H]1N1C(=O)N=C(NO)C(C=CBr)=C1 Chemical compound O1[C@H](CO)C[C@@H](O)[C@@H]1N1C(=O)N=C(NO)C(C=CBr)=C1 ZAEILDGYYKZLQP-QXFUBDJGSA-N 0.000 description 1
- VAQJLQIHOPGCRG-VAOFZXAKSA-N O1[C@H](CO)C[C@@H](O)[C@@H]1N1C(=O)N=C(NO)C(C=CC(O)=O)=C1 Chemical compound O1[C@H](CO)C[C@@H](O)[C@@H]1N1C(=O)N=C(NO)C(C=CC(O)=O)=C1 VAQJLQIHOPGCRG-VAOFZXAKSA-N 0.000 description 1
- KVUGKZDEBWHGRL-QXFUBDJGSA-N O1[C@H](CO)C[C@@H](O)[C@@H]1N1C(=O)N=C(NO)C(C=CCl)=C1 Chemical compound O1[C@H](CO)C[C@@H](O)[C@@H]1N1C(=O)N=C(NO)C(C=CCl)=C1 KVUGKZDEBWHGRL-QXFUBDJGSA-N 0.000 description 1
- NDDARGIGTYCVOD-QXFUBDJGSA-N O1[C@H](CO)C[C@@H](O)[C@@H]1N1C(=O)N=C(NO)C(C=CI)=C1 Chemical compound O1[C@H](CO)C[C@@H](O)[C@@H]1N1C(=O)N=C(NO)C(C=CI)=C1 NDDARGIGTYCVOD-QXFUBDJGSA-N 0.000 description 1
- JNQVLASJFKLFLJ-UGKPPGOTSA-N O=C1N=C(NO)C(C=CC(=O)OC)=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 Chemical compound O=C1N=C(NO)C(C=CC(=O)OC)=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 JNQVLASJFKLFLJ-UGKPPGOTSA-N 0.000 description 1
- DYLPAQWVKQJPJL-FDDDBJFASA-N O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)N=C(NO)C(C=CBr)=C1 Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)N=C(NO)C(C=CBr)=C1 DYLPAQWVKQJPJL-FDDDBJFASA-N 0.000 description 1
- MGZZZIPZJXJPFE-PNHWDRBUSA-N O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)N=C(NO)C(C=CC(O)=O)=C1 Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)N=C(NO)C(C=CC(O)=O)=C1 MGZZZIPZJXJPFE-PNHWDRBUSA-N 0.000 description 1
- LUZSQLZATOKPSJ-FDDDBJFASA-N O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)N=C(NO)C(C=CCl)=C1 Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)N=C(NO)C(C=CCl)=C1 LUZSQLZATOKPSJ-FDDDBJFASA-N 0.000 description 1
- YXKTUIIHQLOHDV-FDDDBJFASA-N O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)N=C(NO)C(C=CI)=C1 Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)N=C(NO)C(C=CI)=C1 YXKTUIIHQLOHDV-FDDDBJFASA-N 0.000 description 1
- 241000711502 Paramyxovirinae Species 0.000 description 1
- 229910002666 PdCl2 Inorganic materials 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- 201000011152 Pemphigus Diseases 0.000 description 1
- 241000711558 Pestivirus type 3 Species 0.000 description 1
- 241000283216 Phocidae Species 0.000 description 1
- 206010035664 Pneumonia Diseases 0.000 description 1
- 241000711902 Pneumovirus Species 0.000 description 1
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 1
- 101710188315 Protein X Proteins 0.000 description 1
- PTJWIQPHWPFNBW-UHFFFAOYSA-N Pseudouridine C Natural products OC1C(O)C(CO)OC1C1=CNC(=O)NC1=O PTJWIQPHWPFNBW-UHFFFAOYSA-N 0.000 description 1
- LCTONWCANYUPML-UHFFFAOYSA-M Pyruvate Chemical compound CC(=O)C([O-])=O LCTONWCANYUPML-UHFFFAOYSA-M 0.000 description 1
- 102000009572 RNA Polymerase II Human genes 0.000 description 1
- 108010009460 RNA Polymerase II Proteins 0.000 description 1
- 238000002123 RNA extraction Methods 0.000 description 1
- 238000010802 RNA extraction kit Methods 0.000 description 1
- 238000010240 RT-PCR analysis Methods 0.000 description 1
- 239000007868 Raney catalyst Substances 0.000 description 1
- 229910000564 Raney nickel Inorganic materials 0.000 description 1
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 1
- 238000006680 Reformatsky reaction Methods 0.000 description 1
- 206010038923 Retinopathy Diseases 0.000 description 1
- 241001147432 Rio Bravo virus group Species 0.000 description 1
- 241001533467 Rubulavirus Species 0.000 description 1
- 241000907519 Saboya virus Species 0.000 description 1
- 238000006350 Schiemann fluorination reaction Methods 0.000 description 1
- 241001147424 Seaborne tick-borne virus group Species 0.000 description 1
- 206010040070 Septic Shock Diseases 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- 241000710888 St. Louis encephalitis virus Species 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 229910000831 Steel Inorganic materials 0.000 description 1
- 241000178332 Stratford virus Species 0.000 description 1
- 101710172711 Structural protein Proteins 0.000 description 1
- 241000282887 Suidae Species 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 210000001744 T-lymphocyte Anatomy 0.000 description 1
- 208000034841 Thrombotic Microangiopathies Diseases 0.000 description 1
- IQFYYKKMVGJFEH-XLPZGREQSA-N Thymidine Natural products O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO)[C@@H](O)C1 IQFYYKKMVGJFEH-XLPZGREQSA-N 0.000 description 1
- 208000004006 Tick-borne encephalitis Diseases 0.000 description 1
- ATJFFYVFTNAWJD-UHFFFAOYSA-N Tin Chemical compound [Sn] ATJFFYVFTNAWJD-UHFFFAOYSA-N 0.000 description 1
- 206010052779 Transplant rejections Diseases 0.000 description 1
- 241000907508 Uganda S virus Species 0.000 description 1
- 241000907517 Usutu virus Species 0.000 description 1
- 206010047115 Vasculitis Diseases 0.000 description 1
- XTXRWKRVRITETP-UHFFFAOYSA-N Vinyl acetate Chemical compound CC(=O)OC=C XTXRWKRVRITETP-UHFFFAOYSA-N 0.000 description 1
- 108700005077 Viral Genes Proteins 0.000 description 1
- 108010067390 Viral Proteins Proteins 0.000 description 1
- 206010051511 Viral diarrhoea Diseases 0.000 description 1
- 208000000260 Warts Diseases 0.000 description 1
- 238000007239 Wittig reaction Methods 0.000 description 1
- 241000120645 Yellow fever virus group Species 0.000 description 1
- RANSNKOSWWZYEJ-KQYNXXCUSA-N [(1r,2r,4r,5r)-2-(6-aminopurin-9-yl)-3,6-dioxabicyclo[3.1.0]hexan-4-yl]methanol Chemical compound NC1=NC=NC2=C1N=CN2[C@H]1[C@@H]2O[C@@H]2[C@@H](CO)O1 RANSNKOSWWZYEJ-KQYNXXCUSA-N 0.000 description 1
- UFDBQRCRZDUKSC-BDNRQGISSA-N [(2r,3r,4r,5r)-4-hydroxy-2-(hydroxymethyl)-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-3-yl] methanesulfonate Chemical compound O=C1NC(=O)C(C)=CN1[C@H]1[C@H](O)[C@@H](OS(C)(=O)=O)[C@@H](CO)O1 UFDBQRCRZDUKSC-BDNRQGISSA-N 0.000 description 1
- DRPPXILAEZTYCN-GUIRCDHDSA-N [(2r,3r,4r,5r)-5-(2,4-dioxo-5-phenylpyrimidin-1-yl)-4-hydroxy-2-(hydroxymethyl)oxolan-3-yl] methanesulfonate Chemical compound O[C@@H]1[C@@H](OS(=O)(=O)C)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(C=2C=CC=CC=2)=C1 DRPPXILAEZTYCN-GUIRCDHDSA-N 0.000 description 1
- VVKGKDURDKDKQA-JAGXHNFQSA-N [(2r,3r,4r,5r)-5-(4-amino-5-chloro-2-oxopyrimidin-1-yl)-4-hydroxy-2-(hydroxymethyl)oxolan-3-yl] methanesulfonate Chemical compound O[C@@H]1[C@@H](OS(=O)(=O)C)[C@@H](CO)O[C@H]1N1C(=O)N=C(N)C(Cl)=C1 VVKGKDURDKDKQA-JAGXHNFQSA-N 0.000 description 1
- MEQUETZJGLMUKY-BDNRQGISSA-N [(2r,3r,4r,5r)-5-(4-amino-5-cyano-2-oxopyrimidin-1-yl)-4-hydroxy-2-(hydroxymethyl)oxolan-3-yl] methanesulfonate Chemical compound O[C@@H]1[C@@H](OS(=O)(=O)C)[C@@H](CO)O[C@H]1N1C(=O)N=C(N)C(C#N)=C1 MEQUETZJGLMUKY-BDNRQGISSA-N 0.000 description 1
- KVYYEMHJYCLCNY-SDNRWEOFSA-N [(2r,3r,4r,5r)-5-(4-amino-5-ethenyl-2-oxopyrimidin-1-yl)-4-hydroxy-2-(hydroxymethyl)oxolan-3-yl] methanesulfonate Chemical compound O[C@@H]1[C@@H](OS(=O)(=O)C)[C@@H](CO)O[C@H]1N1C(=O)N=C(N)C(C=C)=C1 KVYYEMHJYCLCNY-SDNRWEOFSA-N 0.000 description 1
- OWHZSAODTHJMCD-JAGXHNFQSA-N [(2r,3r,4r,5r)-5-(4-amino-5-iodo-2-oxopyrimidin-1-yl)-4-hydroxy-2-(hydroxymethyl)oxolan-3-yl] methanesulfonate Chemical compound O[C@@H]1[C@@H](OS(=O)(=O)C)[C@@H](CO)O[C@H]1N1C(=O)N=C(N)C(I)=C1 OWHZSAODTHJMCD-JAGXHNFQSA-N 0.000 description 1
- PMZNPJFICBMBBC-SDNRWEOFSA-N [(2r,3r,4r,5r)-5-(5-acetyl-2,4-dioxopyrimidin-1-yl)-4-hydroxy-2-(hydroxymethyl)oxolan-3-yl] methanesulfonate Chemical compound O=C1NC(=O)C(C(=O)C)=CN1[C@H]1[C@H](O)[C@@H](OS(C)(=O)=O)[C@@H](CO)O1 PMZNPJFICBMBBC-SDNRWEOFSA-N 0.000 description 1
- APICMTXJCIZHHR-SDNRWEOFSA-N [(2r,3r,4r,5r)-5-(5-acetyl-4-amino-2-oxopyrimidin-1-yl)-4-hydroxy-2-(hydroxymethyl)oxolan-3-yl] methanesulfonate Chemical compound O=C1N=C(N)C(C(=O)C)=CN1[C@H]1[C@H](O)[C@@H](OS(C)(=O)=O)[C@@H](CO)O1 APICMTXJCIZHHR-SDNRWEOFSA-N 0.000 description 1
- JDLJPYUYWBTYTF-QGOVLLJGSA-N [(2r,3r,4r,5r)-5-(5-carbamoyl-2,4-dioxopyrimidin-1-yl)-4-hydroxy-2-(hydroxymethyl)oxolan-3-yl] methanesulfonate Chemical compound O[C@@H]1[C@@H](OS(=O)(=O)C)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(C(N)=O)=C1 JDLJPYUYWBTYTF-QGOVLLJGSA-N 0.000 description 1
- BZXOATHJLMLEHI-SDNRWEOFSA-N [(2r,3r,4r,5r)-5-[4-amino-5-(2-chloroethenyl)-2-oxopyrimidin-1-yl]-4-hydroxy-2-(hydroxymethyl)oxolan-3-yl] methanesulfonate Chemical compound O[C@@H]1[C@@H](OS(=O)(=O)C)[C@@H](CO)O[C@H]1N1C(=O)N=C(N)C(C=CCl)=C1 BZXOATHJLMLEHI-SDNRWEOFSA-N 0.000 description 1
- STALWSUONRYIFS-HJQYOEGKSA-N [(2r,3r,4s,5r)-4-acetyloxy-3-bromo-5-(2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methyl acetate Chemical compound CC(=O)O[C@@H]1[C@H](Br)[C@@H](COC(=O)C)O[C@H]1N1C(=O)NC(=O)C=C1 STALWSUONRYIFS-HJQYOEGKSA-N 0.000 description 1
- PEZOQFPNPPJNKA-FBTJUVTCSA-N [(2r,3s,4r)-4,5-diacetyloxy-3-methylsulfonyloxyoxolan-2-yl]methyl acetate Chemical compound CC(=O)OC[C@H]1OC(OC(C)=O)[C@H](OC(C)=O)[C@H]1OS(C)(=O)=O PEZOQFPNPPJNKA-FBTJUVTCSA-N 0.000 description 1
- DDYPPFKMZRQFCB-WCGPTHBMSA-N [(2r,3s,4s,5r)-2-(2-amino-6-chloropurin-9-yl)-4-bromo-5-(hydroxymethyl)oxolan-3-yl] acetate Chemical compound CC(=O)O[C@@H]1[C@@H](Br)[C@@H](CO)O[C@H]1N1C2=NC(N)=NC(Cl)=C2N=C1 DDYPPFKMZRQFCB-WCGPTHBMSA-N 0.000 description 1
- MWOKLZOHSVYHHW-WCGPTHBMSA-N [(2r,3s,4s,5r)-2-(2-amino-6-oxo-3h-purin-9-yl)-4-bromo-5-(hydroxymethyl)oxolan-3-yl] acetate Chemical compound CC(=O)O[C@@H]1[C@@H](Br)[C@@H](CO)O[C@H]1N1C(N=C(N)NC2=O)=C2N=C1 MWOKLZOHSVYHHW-WCGPTHBMSA-N 0.000 description 1
- IKIQKWREROJYHH-WCGPTHBMSA-N [(2r,3s,4s,5r)-4-bromo-2-(2,6-dichloropurin-9-yl)-5-(hydroxymethyl)oxolan-3-yl] acetate Chemical compound CC(=O)O[C@@H]1[C@@H](Br)[C@@H](CO)O[C@H]1N1C2=NC(Cl)=NC(Cl)=C2N=C1 IKIQKWREROJYHH-WCGPTHBMSA-N 0.000 description 1
- JPTVIMYEBXVLFK-MCOZSMFQSA-N [(2r,3s,4s,5r)-4-bromo-2-(6-chloropurin-9-yl)-5-(hydroxymethyl)oxolan-3-yl] acetate Chemical compound CC(=O)O[C@@H]1[C@@H](Br)[C@@H](CO)O[C@H]1N1C2=NC=NC(Cl)=C2N=C1 JPTVIMYEBXVLFK-MCOZSMFQSA-N 0.000 description 1
- QKGXYAHWALKXKB-DHWQRIIYSA-N [(2r,3s,4s,5r)-4-bromo-5-(hydroxymethyl)-2-(6-methylsulfanylpurin-9-yl)oxolan-3-yl] acetate Chemical compound C1=NC=2C(SC)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@H](Br)[C@H]1OC(C)=O QKGXYAHWALKXKB-DHWQRIIYSA-N 0.000 description 1
- CFGOXCADNPYLBA-HOSYDEDBSA-N [(2r,3s,5r)-3-acetyloxy-5-[4-(dihydroxyamino)-2-oxopyrimidin-1-yl]oxolan-2-yl]methyl acetate Chemical class C1[C@H](OC(C)=O)[C@@H](COC(=O)C)O[C@H]1N1C(=O)N=C(N(O)O)C=C1 CFGOXCADNPYLBA-HOSYDEDBSA-N 0.000 description 1
- LLZABLQALVYFPJ-GVDBMIGSSA-N [(2r,3s,5r)-3-acetyloxy-5-[4-(hydroxyamino)-2-oxo-5-phenylpyrimidin-1-yl]oxolan-2-yl]methyl acetate Chemical compound C1[C@H](OC(C)=O)[C@@H](COC(=O)C)O[C@H]1N1C(=O)N=C(NO)C(C=2C=CC=CC=2)=C1 LLZABLQALVYFPJ-GVDBMIGSSA-N 0.000 description 1
- VFMVNKXZBGKLBD-HOSYDEDBSA-N [(2r,3s,5r)-3-acetyloxy-5-[4-(hydroxyamino)-2-oxopyrimidin-1-yl]oxolan-2-yl]methyl acetate Chemical compound C1[C@H](OC(C)=O)[C@@H](COC(=O)C)O[C@H]1N1C(=O)N=C(NO)C=C1 VFMVNKXZBGKLBD-HOSYDEDBSA-N 0.000 description 1
- GNXXABLMUCQWSV-YNEHKIRRSA-N [(2r,3s,5r)-3-acetyloxy-5-[4-(hydroxyamino)-5-(2-iodoethenyl)-2-oxopyrimidin-1-yl]oxolan-2-yl]methyl acetate Chemical compound C1[C@H](OC(C)=O)[C@@H](COC(=O)C)O[C@H]1N1C(=O)N=C(NO)C(C=CI)=C1 GNXXABLMUCQWSV-YNEHKIRRSA-N 0.000 description 1
- DZDDPSPXZGJSGD-QJPTWQEYSA-N [(2r,3s,5r)-3-acetyloxy-5-[4-(hydroxyamino)-5-methyl-2-oxopyrimidin-1-yl]oxolan-2-yl]methyl acetate Chemical compound C1[C@H](OC(C)=O)[C@@H](COC(=O)C)O[C@H]1N1C(=O)N=C(NO)C(C)=C1 DZDDPSPXZGJSGD-QJPTWQEYSA-N 0.000 description 1
- JZVCZLIECKLJNJ-YNEHKIRRSA-N [(2r,3s,5r)-3-acetyloxy-5-[5-(2-bromoethenyl)-4-(hydroxyamino)-2-oxopyrimidin-1-yl]oxolan-2-yl]methyl acetate Chemical compound C1[C@H](OC(C)=O)[C@@H](COC(=O)C)O[C@H]1N1C(=O)N=C(NO)C(C=CBr)=C1 JZVCZLIECKLJNJ-YNEHKIRRSA-N 0.000 description 1
- QMGPTJJFIBJVCA-YNEHKIRRSA-N [(2r,3s,5r)-3-acetyloxy-5-[5-(2-chloroethenyl)-4-(hydroxyamino)-2-oxopyrimidin-1-yl]oxolan-2-yl]methyl acetate Chemical compound C1[C@H](OC(C)=O)[C@@H](COC(=O)C)O[C@H]1N1C(=O)N=C(NO)C(C=CCl)=C1 QMGPTJJFIBJVCA-YNEHKIRRSA-N 0.000 description 1
- IQNWBIFMNDRJBE-RCCFBDPRSA-N [(2r,3s,5r)-3-acetyloxy-5-[5-benzyl-4-(hydroxyamino)-2-oxopyrimidin-1-yl]oxolan-2-yl]methyl acetate Chemical compound C1[C@H](OC(C)=O)[C@@H](COC(=O)C)O[C@H]1N1C(=O)N=C(NO)C(CC=2C=CC=CC=2)=C1 IQNWBIFMNDRJBE-RCCFBDPRSA-N 0.000 description 1
- HYLBVSWQKGVMDF-HBNTYKKESA-N [(2r,3s,5r)-3-acetyloxy-5-[5-bromo-4-(hydroxyamino)-2-oxopyrimidin-1-yl]oxolan-2-yl]methyl acetate Chemical compound C1[C@H](OC(C)=O)[C@@H](COC(=O)C)O[C@H]1N1C(=O)N=C(NO)C(Br)=C1 HYLBVSWQKGVMDF-HBNTYKKESA-N 0.000 description 1
- PIDJWARTQCSJLR-HBNTYKKESA-N [(2r,3s,5r)-3-acetyloxy-5-[5-carbamoyl-4-(hydroxyamino)-2-oxopyrimidin-1-yl]oxolan-2-yl]methyl acetate Chemical compound C1[C@H](OC(C)=O)[C@@H](COC(=O)C)O[C@H]1N1C(=O)N=C(NO)C(C(N)=O)=C1 PIDJWARTQCSJLR-HBNTYKKESA-N 0.000 description 1
- LUVKTRLELNPTDB-HBNTYKKESA-N [(2r,3s,5r)-3-acetyloxy-5-[5-chloro-4-(hydroxyamino)-2-oxopyrimidin-1-yl]oxolan-2-yl]methyl acetate Chemical compound C1[C@H](OC(C)=O)[C@@H](COC(=O)C)O[C@H]1N1C(=O)N=C(NO)C(Cl)=C1 LUVKTRLELNPTDB-HBNTYKKESA-N 0.000 description 1
- VKMHCORDSAWJKC-QJPTWQEYSA-N [(2r,3s,5r)-3-acetyloxy-5-[5-cyano-4-(hydroxyamino)-2-oxopyrimidin-1-yl]oxolan-2-yl]methyl acetate Chemical compound C1[C@H](OC(C)=O)[C@@H](COC(=O)C)O[C@H]1N1C(=O)N=C(NO)C(C#N)=C1 VKMHCORDSAWJKC-QJPTWQEYSA-N 0.000 description 1
- SYANTIRISGQXQK-YNEHKIRRSA-N [(2r,3s,5r)-3-acetyloxy-5-[5-ethenyl-4-(hydroxyamino)-2-oxopyrimidin-1-yl]oxolan-2-yl]methyl acetate Chemical compound C1[C@H](OC(C)=O)[C@@H](COC(=O)C)O[C@H]1N1C(=O)N=C(NO)C(C=C)=C1 SYANTIRISGQXQK-YNEHKIRRSA-N 0.000 description 1
- YJFSDUJIQNRVOI-YNEHKIRRSA-N [(2r,3s,5r)-3-acetyloxy-5-[5-ethynyl-4-(hydroxyamino)-2-oxopyrimidin-1-yl]oxolan-2-yl]methyl acetate Chemical compound C1[C@H](OC(C)=O)[C@@H](COC(=O)C)O[C@H]1N1C(=O)N=C(NO)C(C#C)=C1 YJFSDUJIQNRVOI-YNEHKIRRSA-N 0.000 description 1
- DLENFROQTUPNKU-HBNTYKKESA-N [(2r,3s,5r)-3-acetyloxy-5-[5-fluoro-4-(hydroxyamino)-2-oxopyrimidin-1-yl]oxolan-2-yl]methyl acetate Chemical compound C1[C@H](OC(C)=O)[C@@H](COC(=O)C)O[C@H]1N1C(=O)N=C(NO)C(F)=C1 DLENFROQTUPNKU-HBNTYKKESA-N 0.000 description 1
- IMGFHHDGMHBQFB-YNEHKIRRSA-N [(2r,3s,5r)-5-[5-acetyl-4-(hydroxyamino)-2-oxopyrimidin-1-yl]-3-acetyloxyoxolan-2-yl]methyl acetate Chemical compound C1[C@H](OC(C)=O)[C@@H](COC(=O)C)O[C@H]1N1C(=O)N=C(NO)C(C(C)=O)=C1 IMGFHHDGMHBQFB-YNEHKIRRSA-N 0.000 description 1
- NEMUUTMNORCQQL-HOSYDEDBSA-N [(2s,4r,5r)-4-acetyloxy-5-[4-(hydroxyamino)-2-oxopyrimidin-1-yl]oxolan-2-yl]methyl acetate Chemical class O1[C@H](COC(=O)C)C[C@@H](OC(C)=O)[C@@H]1N1C(=O)N=C(NO)C=C1 NEMUUTMNORCQQL-HOSYDEDBSA-N 0.000 description 1
- MKSZAUGMIGSRNS-UHFFFAOYSA-N [2-dodecanoyloxy-3-[hydroxy-[hydroxy-[[5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy]phosphoryl]oxyphosphoryl]oxypropyl] dodecanoate Chemical compound O1C(COP(O)(=O)OP(O)(=O)OCC(COC(=O)CCCCCCCCCCC)OC(=O)CCCCCCCCCCC)CCC1N1C(=O)NC(=O)C(C)=C1 MKSZAUGMIGSRNS-UHFFFAOYSA-N 0.000 description 1
- YPDSOAPSWYHANB-UHFFFAOYSA-N [N].[F] Chemical compound [N].[F] YPDSOAPSWYHANB-UHFFFAOYSA-N 0.000 description 1
- HDRRAMINWIWTNU-NTSWFWBYSA-N [[(2s,5r)-5-(2-amino-6-oxo-3h-purin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl] phosphono hydrogen phosphate Chemical compound C1=2NC(N)=NC(=O)C=2N=CN1[C@H]1CC[C@@H](COP(O)(=O)OP(O)(=O)OP(O)(O)=O)O1 HDRRAMINWIWTNU-NTSWFWBYSA-N 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- DUVKXNKIYKAUPK-UHFFFAOYSA-N acetic acid;triphenylphosphane Chemical compound CC(O)=O.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 DUVKXNKIYKAUPK-UHFFFAOYSA-N 0.000 description 1
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 1
- 239000012346 acetyl chloride Substances 0.000 description 1
- 238000005903 acid hydrolysis reaction Methods 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 208000017733 acquired polycythemia vera Diseases 0.000 description 1
- 150000001252 acrylic acid derivatives Chemical class 0.000 description 1
- 208000009621 actinic keratosis Diseases 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 229960005305 adenosine Drugs 0.000 description 1
- 210000001789 adipocyte Anatomy 0.000 description 1
- PYMYPHUHKUWMLA-WISUUJSJSA-N aldehydo-L-xylose Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)C=O PYMYPHUHKUWMLA-WISUUJSJSA-N 0.000 description 1
- 229930195726 aldehydo-L-xylose Natural products 0.000 description 1
- 150000004703 alkoxides Chemical class 0.000 description 1
- 125000005907 alkyl ester group Chemical group 0.000 description 1
- 150000001351 alkyl iodides Chemical class 0.000 description 1
- 125000000746 allylic group Chemical group 0.000 description 1
- AWUCVROLDVIAJX-UHFFFAOYSA-N alpha-glycerophosphate Natural products OCC(O)COP(O)(O)=O AWUCVROLDVIAJX-UHFFFAOYSA-N 0.000 description 1
- 150000001414 amino alcohols Chemical class 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 229940107816 ammonium iodide Drugs 0.000 description 1
- 238000005915 ammonolysis reaction Methods 0.000 description 1
- 230000003698 anagen phase Effects 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000004037 angiogenesis inhibitor Substances 0.000 description 1
- 230000002491 angiogenic effect Effects 0.000 description 1
- UMDFLFHAXYPYQN-UKTARXLSSA-N anhydro nucleoside Chemical compound C([C@H]1O[C@H]2N3C=C(C(N=C3O[C@@H]1[C@@H]2F)=O)C)OC(=O)C1=CC=CC=C1 UMDFLFHAXYPYQN-UKTARXLSSA-N 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 230000003466 anti-cipated effect Effects 0.000 description 1
- 230000003602 anti-herpes Effects 0.000 description 1
- 230000036436 anti-hiv Effects 0.000 description 1
- 230000000798 anti-retroviral effect Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 239000000427 antigen Substances 0.000 description 1
- 230000027645 antigenic variation Effects 0.000 description 1
- 108091007433 antigens Proteins 0.000 description 1
- 102000036639 antigens Human genes 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 239000012062 aqueous buffer Substances 0.000 description 1
- 150000001491 aromatic compounds Chemical class 0.000 description 1
- 210000001367 artery Anatomy 0.000 description 1
- 229940072107 ascorbate Drugs 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 230000003143 atherosclerotic effect Effects 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- 201000008937 atopic dermatitis Diseases 0.000 description 1
- 150000001540 azides Chemical class 0.000 description 1
- 150000007514 bases Chemical class 0.000 description 1
- 208000003373 basosquamous carcinoma Diseases 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- WPUJEWVVTKLMQI-UHFFFAOYSA-N benzene;ethoxyethane Chemical compound CCOCC.C1=CC=CC=C1 WPUJEWVVTKLMQI-UHFFFAOYSA-N 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- SRBFZHDQGSBBOR-UHFFFAOYSA-N beta-D-Pyranose-Lyxose Natural products OC1COC(O)C(O)C1O SRBFZHDQGSBBOR-UHFFFAOYSA-N 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 238000010170 biological method Methods 0.000 description 1
- 239000004305 biphenyl Substances 0.000 description 1
- 235000010290 biphenyl Nutrition 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- MCQRPQCQMGVWIQ-UHFFFAOYSA-N boron;methylsulfanylmethane Chemical compound [B].CSC MCQRPQCQMGVWIQ-UHFFFAOYSA-N 0.000 description 1
- 230000031709 bromination Effects 0.000 description 1
- 238000005893 bromination reaction Methods 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- LUZSPGQEISANPO-UHFFFAOYSA-N butyltin Chemical class CCCC[Sn] LUZSPGQEISANPO-UHFFFAOYSA-N 0.000 description 1
- 229910052792 caesium Inorganic materials 0.000 description 1
- TVFDJXOCXUVLDH-UHFFFAOYSA-N caesium atom Chemical compound [Cs] TVFDJXOCXUVLDH-UHFFFAOYSA-N 0.000 description 1
- 150000001669 calcium Chemical class 0.000 description 1
- 208000035269 cancer or benign tumor Diseases 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 235000014633 carbohydrates Nutrition 0.000 description 1
- 150000005323 carbonate salts Chemical class 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 230000030833 cell death Effects 0.000 description 1
- 230000003915 cell function Effects 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 230000012292 cell migration Effects 0.000 description 1
- 239000013553 cell monolayer Substances 0.000 description 1
- VYLVYHXQOHJDJL-UHFFFAOYSA-K cerium trichloride Chemical compound Cl[Ce](Cl)Cl VYLVYHXQOHJDJL-UHFFFAOYSA-K 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- LRCIYVMVWAMTKX-UHFFFAOYSA-L chromium(ii) acetate Chemical compound [Cr+2].CC([O-])=O.CC([O-])=O LRCIYVMVWAMTKX-UHFFFAOYSA-L 0.000 description 1
- 230000007882 cirrhosis Effects 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 238000011260 co-administration Methods 0.000 description 1
- 229920001436 collagen Polymers 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 229940126543 compound 14 Drugs 0.000 description 1
- 238000013329 compounding Methods 0.000 description 1
- 108091036078 conserved sequence Proteins 0.000 description 1
- 238000011109 contamination Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 description 1
- 238000005100 correlation spectroscopy Methods 0.000 description 1
- 238000011942 cross aldol reaction Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 239000012228 culture supernatant Substances 0.000 description 1
- HPXRVTGHNJAIIH-UHFFFAOYSA-N cyclohexanol Chemical compound OC1CCCCC1 HPXRVTGHNJAIIH-UHFFFAOYSA-N 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000004210 cyclohexylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- HAAZLUGHYHWQIW-KVQBGUIXSA-N dGTP Chemical compound C1=NC=2C(=O)NC(N)=NC=2N1[C@H]1C[C@H](O)[C@@H](COP(O)(=O)OP(O)(=O)OP(O)(O)=O)O1 HAAZLUGHYHWQIW-KVQBGUIXSA-N 0.000 description 1
- 238000007256 debromination reaction Methods 0.000 description 1
- 238000006114 decarboxylation reaction Methods 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 208000025729 dengue disease Diseases 0.000 description 1
- 238000006392 deoxygenation reaction Methods 0.000 description 1
- 238000001212 derivatisation Methods 0.000 description 1
- 229910052805 deuterium Inorganic materials 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- RAFNCPHFRHZCPS-UHFFFAOYSA-N di(imidazol-1-yl)methanethione Chemical compound C1=CN=CN1C(=S)N1C=CN=C1 RAFNCPHFRHZCPS-UHFFFAOYSA-N 0.000 description 1
- 208000033679 diabetic kidney disease Diseases 0.000 description 1
- 238000000502 dialysis Methods 0.000 description 1
- 229910003460 diamond Inorganic materials 0.000 description 1
- 239000010432 diamond Substances 0.000 description 1
- 238000006193 diazotization reaction Methods 0.000 description 1
- FHHZOYXKOICLGH-UHFFFAOYSA-N dichloromethane;ethanol Chemical compound CCO.ClCCl FHHZOYXKOICLGH-UHFFFAOYSA-N 0.000 description 1
- NPOMSUOUAZCMBL-UHFFFAOYSA-N dichloromethane;ethoxyethane Chemical compound ClCCl.CCOCC NPOMSUOUAZCMBL-UHFFFAOYSA-N 0.000 description 1
- OUFFZTAHNSOGKX-UHFFFAOYSA-L dichloropalladium;lithium Chemical compound [Li].Cl[Pd]Cl OUFFZTAHNSOGKX-UHFFFAOYSA-L 0.000 description 1
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- VAYGXNSJCAHWJZ-UHFFFAOYSA-N dimethyl sulfate Chemical compound COS(=O)(=O)OC VAYGXNSJCAHWJZ-UHFFFAOYSA-N 0.000 description 1
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 1
- YWWZCHLUQSHMCL-UHFFFAOYSA-N diphenyl diselenide Chemical compound C=1C=CC=CC=1[Se][Se]C1=CC=CC=C1 YWWZCHLUQSHMCL-UHFFFAOYSA-N 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 238000006073 displacement reaction Methods 0.000 description 1
- 238000000921 elemental analysis Methods 0.000 description 1
- 239000012149 elution buffer Substances 0.000 description 1
- 206010014599 encephalitis Diseases 0.000 description 1
- 210000003038 endothelium Anatomy 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- JOZGNYDSEBIJDH-UHFFFAOYSA-N eniluracil Chemical compound O=C1NC=C(C#C)C(=O)N1 JOZGNYDSEBIJDH-UHFFFAOYSA-N 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- GKIPXFAANLTWBM-UHFFFAOYSA-N epibromohydrin Chemical compound BrCC1CO1 GKIPXFAANLTWBM-UHFFFAOYSA-N 0.000 description 1
- 210000001339 epidermal cell Anatomy 0.000 description 1
- 210000002615 epidermis Anatomy 0.000 description 1
- 239000003797 essential amino acid Substances 0.000 description 1
- 235000020776 essential amino acid Nutrition 0.000 description 1
- 239000000469 ethanolic extract Substances 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- MDKXBBPLEGPIRI-UHFFFAOYSA-N ethoxyethane;methanol Chemical compound OC.CCOCC MDKXBBPLEGPIRI-UHFFFAOYSA-N 0.000 description 1
- YPAATPPIKLIQGE-UHFFFAOYSA-N ethoxymethylidene(triphenyl)-$l^{5}-phosphane Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)(=COCC)C1=CC=CC=C1 YPAATPPIKLIQGE-UHFFFAOYSA-N 0.000 description 1
- DEPWYOAZHVUBJN-YNEHKIRRSA-N ethyl 1-[(2r,4s,5r)-4-acetyloxy-5-(acetyloxymethyl)oxolan-2-yl]-4-(hydroxyamino)-2-oxopyrimidine-5-carboxylate Chemical compound O=C1N=C(NO)C(C(=O)OCC)=CN1[C@@H]1O[C@H](COC(C)=O)[C@@H](OC(C)=O)C1 DEPWYOAZHVUBJN-YNEHKIRRSA-N 0.000 description 1
- CTLAIKSGNQPPLO-UHFFFAOYSA-N ethyl cyclopent-3-ene-1-carboxylate Chemical compound CCOC(=O)C1CC=CC1 CTLAIKSGNQPPLO-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 231100000573 exposure to toxins Toxicity 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000012091 fetal bovine serum Substances 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 238000003682 fluorination reaction Methods 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 125000003843 furanosyl group Chemical group 0.000 description 1
- 230000014509 gene expression Effects 0.000 description 1
- 238000010353 genetic engineering Methods 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 150000002334 glycols Chemical class 0.000 description 1
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 1
- 229910052737 gold Inorganic materials 0.000 description 1
- 239000010931 gold Substances 0.000 description 1
- 239000003979 granulating agent Substances 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 230000026030 halogenation Effects 0.000 description 1
- 238000005658 halogenation reaction Methods 0.000 description 1
- DMEGYFMYUHOHGS-UHFFFAOYSA-N heptamethylene Natural products C1CCCCCC1 DMEGYFMYUHOHGS-UHFFFAOYSA-N 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 201000008298 histiocytosis Diseases 0.000 description 1
- 230000036571 hydration Effects 0.000 description 1
- 238000006703 hydration reaction Methods 0.000 description 1
- 150000004678 hydrides Chemical class 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical group 0.000 description 1
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 1
- 238000007031 hydroxymethylation reaction Methods 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 230000002779 inactivation Effects 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 208000037800 influenza D Diseases 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 239000003999 initiator Substances 0.000 description 1
- 239000002198 insoluble material Substances 0.000 description 1
- 229960003521 interferon alfa-2a Drugs 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-M iodide Chemical compound [I-] XMBWDFGMSWQBCA-UHFFFAOYSA-M 0.000 description 1
- 229940006461 iodide ion Drugs 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000004491 isohexyl group Chemical group C(CCC(C)C)* 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 208000017169 kidney disease Diseases 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- CFHGBZLNZZVTAY-UHFFFAOYSA-N lawesson's reagent Chemical compound C1=CC(OC)=CC=C1P1(=S)SP(=S)(C=2C=CC(OC)=CC=2)S1 CFHGBZLNZZVTAY-UHFFFAOYSA-N 0.000 description 1
- 150000007517 lewis acids Chemical class 0.000 description 1
- 201000011486 lichen planus Diseases 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 239000002502 liposome Substances 0.000 description 1
- 238000006138 lithiation reaction Methods 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 208000019423 liver disease Diseases 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 238000000464 low-speed centrifugation Methods 0.000 description 1
- 208000030500 lower respiratory tract disease Diseases 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 201000005202 lung cancer Diseases 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 238000013160 medical therapy Methods 0.000 description 1
- 210000004779 membrane envelope Anatomy 0.000 description 1
- BRMYZIKAHFEUFJ-UHFFFAOYSA-L mercury diacetate Chemical compound CC(=O)O[Hg]OC(C)=O BRMYZIKAHFEUFJ-UHFFFAOYSA-L 0.000 description 1
- 210000003584 mesangial cell Anatomy 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 238000006263 metalation reaction Methods 0.000 description 1
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Natural products C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 1
- HGPYZCBYEUEITD-UHFFFAOYSA-N methyl 3-(4-acetyl-4-amino-2-oxo-1,3-dihydropyrimidin-5-yl)prop-2-enoate Chemical compound C(C)(=O)C1(NC(NC=C1C=CC(=O)OC)=O)N HGPYZCBYEUEITD-UHFFFAOYSA-N 0.000 description 1
- KQRVBQASADQWPL-UHFFFAOYSA-N methyl 3-(4-amino-4-benzoyl-2-oxo-1,3-dihydropyrimidin-5-yl)prop-2-enoate Chemical compound C(C1=CC=CC=C1)(=O)C1(NC(NC=C1C=CC(=O)OC)=O)N KQRVBQASADQWPL-UHFFFAOYSA-N 0.000 description 1
- RPVXVNPRFDNXGA-UGKPPGOTSA-N methyl 3-[1-[(2r,3r,4r,5r)-4-hydroxy-5-(hydroxymethyl)-3-iodooxolan-2-yl]-2,4-dioxopyrimidin-5-yl]prop-2-enoate Chemical compound O=C1NC(=O)C(C=CC(=O)OC)=CN1[C@H]1[C@H](I)[C@H](O)[C@@H](CO)O1 RPVXVNPRFDNXGA-UGKPPGOTSA-N 0.000 description 1
- SRDWACJPMFQCAC-UGKPPGOTSA-N methyl 3-[1-[(2r,3s,4s,5r)-3-hydroxy-5-(hydroxymethyl)-4-iodooxolan-2-yl]-2,4-dioxopyrimidin-5-yl]prop-2-enoate Chemical compound O=C1NC(=O)C(C=CC(=O)OC)=CN1[C@H]1[C@H](O)[C@H](I)[C@@H](CO)O1 SRDWACJPMFQCAC-UGKPPGOTSA-N 0.000 description 1
- JMJPAHOVQHUZIQ-BFHYXJOUSA-N methyl 3-[1-[(2r,4s,5r)-4-acetyloxy-5-(acetyloxymethyl)oxolan-2-yl]-4-(hydroxyamino)-2-oxopyrimidin-5-yl]prop-2-enoate Chemical compound O=C1N=C(NO)C(C=CC(=O)OC)=CN1[C@@H]1O[C@H](COC(C)=O)[C@@H](OC(C)=O)C1 JMJPAHOVQHUZIQ-BFHYXJOUSA-N 0.000 description 1
- QZUOHIKEIQWFBD-YGOYTEALSA-N methyl 3-[4-(hydroxyamino)-1-[(2R,3R,5S)-3-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-2-oxopyrimidin-5-yl]prop-2-enoate Chemical compound O=C1N=C(NO)C(C=CC(=O)OC)=CN1[C@H]1[C@H](O)C[C@@H](CO)O1 QZUOHIKEIQWFBD-YGOYTEALSA-N 0.000 description 1
- DSPUVJYUMAIFNT-UHFFFAOYSA-N methyl 3-[6-(hydroxyamino)-2-oxo-1H-pyrimidin-5-yl]prop-2-enoate Chemical compound O(C)C(=O)C=CC=1C(=NC(NC=1)=O)NO DSPUVJYUMAIFNT-UHFFFAOYSA-N 0.000 description 1
- VZZPQCRPTSARGE-UHFFFAOYSA-N methyl 3-[6-[(4-methoxybenzoyl)amino]-2-oxo-1H-pyrimidin-5-yl]prop-2-enoate Chemical compound COC(=O)C=Cc1c[nH]c(=O)nc1NC(=O)c1ccc(OC)cc1 VZZPQCRPTSARGE-UHFFFAOYSA-N 0.000 description 1
- 230000011987 methylation Effects 0.000 description 1
- 238000007069 methylation reaction Methods 0.000 description 1
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 1
- 244000000010 microbial pathogen Species 0.000 description 1
- PJUIMOJAAPLTRJ-UHFFFAOYSA-N monothioglycerol Chemical compound OCC(O)CS PJUIMOJAAPLTRJ-UHFFFAOYSA-N 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- 208000031225 myocardial ischemia Diseases 0.000 description 1
- ZQRBSCXRHDJZBS-UHFFFAOYSA-N n,n-dibutylbutan-1-amine;hydrofluoride Chemical compound F.CCCCN(CCCC)CCCC ZQRBSCXRHDJZBS-UHFFFAOYSA-N 0.000 description 1
- BXJVBCCMZKYRGE-UHFFFAOYSA-N n,n-dimethyl-7h-purin-2-amine Chemical compound CN(C)C1=NC=C2NC=NC2=N1 BXJVBCCMZKYRGE-UHFFFAOYSA-N 0.000 description 1
- GJVGFUHRDNNOJI-UHFFFAOYSA-N n-[5-(2-chloroethenyl)-2-oxo-1h-pyrimidin-6-yl]-4-methoxybenzamide Chemical compound C1=CC(OC)=CC=C1C(=O)NC1=C(C=CCl)C=NC(=O)N1 GJVGFUHRDNNOJI-UHFFFAOYSA-N 0.000 description 1
- CBHDSHHPORVUOH-GZCUOZMLSA-N n-[6-chloro-1-[(2r,3r,4r,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]purin-2-yl]acetamide Chemical compound CC(=O)NC1=NC2=NC=NC2=C(Cl)N1[C@@H]1O[C@H](CO)[C@H](O)[C@H]1O CBHDSHHPORVUOH-GZCUOZMLSA-N 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 201000009925 nephrosclerosis Diseases 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 238000006396 nitration reaction Methods 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 description 1
- 230000037311 normal skin Effects 0.000 description 1
- 238000010899 nucleation Methods 0.000 description 1
- 239000012434 nucleophilic reagent Substances 0.000 description 1
- 238000010534 nucleophilic substitution reaction Methods 0.000 description 1
- 229940127073 nucleoside analogue Drugs 0.000 description 1
- KOSYAAIZOGNATQ-UHFFFAOYSA-N o-phenyl chloromethanethioate Chemical compound ClC(=S)OC1=CC=CC=C1 KOSYAAIZOGNATQ-UHFFFAOYSA-N 0.000 description 1
- PIDFDZJZLOTZTM-KHVQSSSXSA-N ombitasvir Chemical compound COC(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@H]1C(=O)NC1=CC=C([C@H]2N([C@@H](CC2)C=2C=CC(NC(=O)[C@H]3N(CCC3)C(=O)[C@@H](NC(=O)OC)C(C)C)=CC=2)C=2C=CC(=CC=2)C(C)(C)C)C=C1 PIDFDZJZLOTZTM-KHVQSSSXSA-N 0.000 description 1
- 239000007935 oral tablet Substances 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 239000012285 osmium tetroxide Substances 0.000 description 1
- 229910000489 osmium tetroxide Inorganic materials 0.000 description 1
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 description 1
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 201000001976 pemphigus vulgaris Diseases 0.000 description 1
- 230000035515 penetration Effects 0.000 description 1
- XNLICIUVMPYHGG-UHFFFAOYSA-N pentan-2-one Chemical compound CCCC(C)=O XNLICIUVMPYHGG-UHFFFAOYSA-N 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 150000002978 peroxides Chemical class 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 150000002989 phenols Chemical class 0.000 description 1
- 125000000286 phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000002467 phosphate group Chemical group [H]OP(=O)(O[H])O[*] 0.000 description 1
- 150000003014 phosphoric acid esters Chemical class 0.000 description 1
- CYQAYERJWZKYML-UHFFFAOYSA-N phosphorus pentasulfide Chemical compound S1P(S2)(=S)SP3(=S)SP1(=S)SP2(=S)S3 CYQAYERJWZKYML-UHFFFAOYSA-N 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 230000008488 polyadenylation Effects 0.000 description 1
- 208000037244 polycythemia vera Diseases 0.000 description 1
- 238000012987 post-synthetic modification Methods 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- NNFCIKHAZHQZJG-UHFFFAOYSA-N potassium cyanide Chemical compound [K+].N#[C-] NNFCIKHAZHQZJG-UHFFFAOYSA-N 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- PTJWIQPHWPFNBW-GBNDHIKLSA-N pseudouridine Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1C1=CNC(=O)NC1=O PTJWIQPHWPFNBW-GBNDHIKLSA-N 0.000 description 1
- IGFXRKMLLMBKSA-UHFFFAOYSA-N purine Chemical compound N1=C[N]C2=NC=NC2=C1 IGFXRKMLLMBKSA-UHFFFAOYSA-N 0.000 description 1
- 150000003834 purine nucleoside derivatives Chemical class 0.000 description 1
- 239000012217 radiopharmaceutical Substances 0.000 description 1
- 229940121896 radiopharmaceutical Drugs 0.000 description 1
- 230000002799 radiopharmaceutical effect Effects 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000009877 rendering Methods 0.000 description 1
- 208000037803 restenosis Diseases 0.000 description 1
- 125000000548 ribosyl group Chemical class C1([C@H](O)[C@H](O)[C@H](O1)CO)* 0.000 description 1
- DWRXFEITVBNRMK-JXOAFFINSA-N ribothymidine Chemical compound O=C1NC(=O)C(C)=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 DWRXFEITVBNRMK-JXOAFFINSA-N 0.000 description 1
- 238000007142 ring opening reaction Methods 0.000 description 1
- 239000012047 saturated solution Substances 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 238000007423 screening assay Methods 0.000 description 1
- 239000012363 selectfluor Substances 0.000 description 1
- 150000003346 selenoethers Chemical class 0.000 description 1
- 230000036303 septic shock Effects 0.000 description 1
- 238000013207 serial dilution Methods 0.000 description 1
- DOQQTKLDEQSKIE-UHFFFAOYSA-N silver;isocyanate Chemical compound [Ag+].[N-]=C=O DOQQTKLDEQSKIE-UHFFFAOYSA-N 0.000 description 1
- 125000003808 silyl group Chemical group [H][Si]([H])([H])[*] 0.000 description 1
- 210000004927 skin cell Anatomy 0.000 description 1
- 208000017520 skin disease Diseases 0.000 description 1
- 201000010153 skin papilloma Diseases 0.000 description 1
- 210000002460 smooth muscle Anatomy 0.000 description 1
- 210000000329 smooth muscle myocyte Anatomy 0.000 description 1
- AWUCVROLDVIAJX-GSVOUGTGSA-N sn-glycerol 3-phosphate Chemical compound OC[C@@H](O)COP(O)(O)=O AWUCVROLDVIAJX-GSVOUGTGSA-N 0.000 description 1
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 1
- 239000004299 sodium benzoate Substances 0.000 description 1
- 235000010234 sodium benzoate Nutrition 0.000 description 1
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Substances [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- HYHCSLBZRBJJCH-UHFFFAOYSA-M sodium hydrosulfide Chemical compound [Na+].[SH-] HYHCSLBZRBJJCH-UHFFFAOYSA-M 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000010959 steel Substances 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 239000012089 stop solution Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- HXJUTPCZVOIRIF-UHFFFAOYSA-N sulfolane Chemical compound O=S1(=O)CCCC1 HXJUTPCZVOIRIF-UHFFFAOYSA-N 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- DKVBOUDTNWVDEP-NJCHZNEYSA-N teicoplanin aglycone Chemical compound N([C@H](C(N[C@@H](C1=CC(O)=CC(O)=C1C=1C(O)=CC=C2C=1)C(O)=O)=O)[C@H](O)C1=CC=C(C(=C1)Cl)OC=1C=C3C=C(C=1O)OC1=CC=C(C=C1Cl)C[C@H](C(=O)N1)NC([C@H](N)C=4C=C(O5)C(O)=CC=4)=O)C(=O)[C@@H]2NC(=O)[C@@H]3NC(=O)[C@@H]1C1=CC5=CC(O)=C1 DKVBOUDTNWVDEP-NJCHZNEYSA-N 0.000 description 1
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 238000005979 thermal decomposition reaction Methods 0.000 description 1
- 125000004001 thioalkyl group Chemical group 0.000 description 1
- 229940035024 thioglycerol Drugs 0.000 description 1
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 230000002103 transcriptional effect Effects 0.000 description 1
- 238000011269 treatment regimen Methods 0.000 description 1
- YWBFPKPWMSWWEA-UHFFFAOYSA-O triazolopyrimidine Chemical compound BrC1=CC=CC(C=2N=C3N=CN[N+]3=C(NCC=3C=CN=CC=3)C=2)=C1 YWBFPKPWMSWWEA-UHFFFAOYSA-O 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 1
- VPAYJEUHKVESSD-UHFFFAOYSA-N trifluoroiodomethane Chemical compound FC(F)(F)I VPAYJEUHKVESSD-UHFFFAOYSA-N 0.000 description 1
- 238000001665 trituration Methods 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 108010087967 type I signal peptidase Proteins 0.000 description 1
- 241001430294 unidentified retrovirus Species 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 230000000982 vasogenic effect Effects 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 210000003501 vero cell Anatomy 0.000 description 1
- 244000052613 viral pathogen Species 0.000 description 1
- 210000002845 virion Anatomy 0.000 description 1
- 238000012800 visualization Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- HBOMLICNUCNMMY-XLPZGREQSA-N zidovudine Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO)[C@@H](N=[N+]=[N-])C1 HBOMLICNUCNMMY-XLPZGREQSA-N 0.000 description 1
- 229960002555 zidovudine Drugs 0.000 description 1
- 150000004799 α-ketoamides Chemical class 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/16—Purine radicals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
- A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
- A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
- A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
- A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
- A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
- A61K31/7076—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines containing purines, e.g. adenosine, adenylic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/06—Antipsoriatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/12—Keratolytics, e.g. wart or anti-corn preparations
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/12—Drugs for disorders of the metabolism for electrolyte homeostasis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/048—Pyridine radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/06—Pyrimidine radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/06—Pyrimidine radicals
- C07H19/10—Pyrimidine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/16—Purine radicals
- C07H19/20—Purine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H21/00—Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids
- C07H21/04—Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids with deoxyribosyl as saccharide radical
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
- C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
- C12Q1/6809—Methods for determination or identification of nucleic acids involving differential detection
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
- C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
- C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
- C12Q1/6888—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for detection or identification of organisms
- C12Q1/689—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for detection or identification of organisms for bacteria
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
- C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
- C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
- C12Q1/6888—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for detection or identification of organisms
- C12Q1/6895—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for detection or identification of organisms for plants, fungi or algae
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Definitions
- the present invention includes compounds and methods for the treatment of Flaviviridae, Orthomyxoviridae, Paramyxoviridae infections and abnormal cellular proliferation.
- the Flaviviridae is a group of positive single-stranded RNA viruses with a genome size from 9-15 kb. They are enveloped viruses of approximately 40-50 nm. An overview of the Flaviviridae taxonomy is available from the International Committee for Taxonomy of Viruses. The Flaviviridae consists of three genera.
- Flavi viruses This genus includes the Dengue virus group (Dengue virus, Dengue virus type 1, Dengue virus type 2, Dengue virus type 3, Dengue virus type 4), the Japanese encephalitis virus group (Alfuy Virus, Japanese encephalitis virus, Kookaburra virus, Koutango virus, Kunjin virus, Murray Valley encephalitis virus, St.
- Dengue virus group Dengue virus, Dengue virus type 1, Dengue virus type 2, Dengue virus type 3, Dengue virus type 4
- the Japanese encephalitis virus group Alfuy Virus, Japanese encephalitis virus, Kookaburra virus, Koutango virus, Kunjin virus, Murray Valley encephalitis virus, St.
- HCV Hepatitis C virus
- BVDV-2 Bovine Viral Diarrhea Nirus-2
- Pestivirus type 1 (including BVDV), Pestivirus type 2 (including Hog Cholera Virus) and Pestivirus type 3 (including Border Disease Virus).
- HCV hepatitis C virus
- HCV hepatitis C virus
- the translated polyprotein contains the structural core (C) and envelope proteins (El, E2, p7) at the ⁇ -terminus, followed by the nonstructural proteins ( ⁇ S2, NS3, NS4A, NS4B, NS5A, NS5B).
- the mature structural proteins are generated via cleavage by the host signal peptidase (see: Hijikata, M. et al. Proc. Nat. Acad. Sci., USA, 1991, 88, 5547; Hussy, P. et al. Virology, 1996, 224, 93; Lin, C. et al. J. Virol, 1994, 68, 5063; Mizushima, H. et al. J.
- NS3 complexed with NS4A contains the NTP-dependent helicase activity which unwinds duplex RNA during replication.
- RNA-dependent RNA polymerase (RDRP) activity (see: Behrens, S. E. et al. EMBO J., 1996, 15, 12; Lohmann, V. et al. J. Virol, 1997, 71, 8416-8428 and Lohmann, V. et al. Virology, 1998, 249, 108), which is essential for viral replication. (Ferrari, E. et al. L Virol, 1999, 73, 1649) It is emphasized here that, unlike HBV or HIV, no DNA is involved in the replication of HCV.
- RDRP RNA- dependent RNA polymerase
- HCV-RDRP substrate specificity for HCV-RDRP was studied using guanosine 5'-monophosphate (GMP), 5'- diphosphate (GDP), 5'-tri ⁇ hosphate (GTP) and the 5'-triphosphate of 2'-deoxy and 2 ⁇ 3'- dideoxy guanosine (dGTP and ddGTP, respectively).
- GMP guanosine 5'-monophosphate
- GDP 5'- diphosphate
- GTP 5'-tri ⁇ hosphate
- dGTP and ddGTP 2'-deoxy and 2 ⁇ 3'- dideoxy guanosine
- antiviral agents that have been identified as active against the hepatitis C flavivirus include:
- Substrate-based NS3 protease inhibitors (Attwood et al. PCT WO 98/22496, 1998; Attwood et al. Antiviral Chemistry and Chemotherapy 1999, 10, 259, ; Attwood et al. German Patent Publication DE 19914474; Tung et al. PCT WO 98/17679), including alphaketoamides and hydrazinoureas, and inhibitors that terminate in an electrophile such as a boronic acid or phosphonate (Llinas- Brunet et. al. PCT WO 99/07734);
- Non-substrate-based inhibitors such as 2,4,6-trihydroxy-3-nitro-benzamide derivatives (Sudo K. et al, Biochemical and Biophysical Research Communications, 1997, 238, 643 and Sudo K. et al. Antiviral Chemistry and Chemotherapy 1998, 9, 186), including RD3-4082 and RD3-4078, the former substituted on the amide with a 14 carbon chain and the latter processing a jD ⁇ r ⁇ -phenoxyphenyl group;
- HCV helicase inhibitors (Diana G. D. et al, U.S. Patent No. 5,633,358 and Diana G. D. et al. PCT WO 97/36554);
- HCV polymerase inhibitors such as nucleotide analogues, gliotoxin (Ferrari R. et al. Journal of Virology 1999, 73, 1649), and the natural product cerulenin (Lohmann V. et al. Virology 1998, 249, 108);
- Antisense phosphorothioate oligodeoxynucleotides complementary to at least a portion of a sequence of the HCV (Anderson et al. U.S. Patent No. 6,174,868), and in particular the sequence stretches in the 5' non-coding region (NCR) (Alt M. et al. Hepatology 1995, 22, 707), or nucleotides 326-348 comprising the 3' end of the NCR and nucleotides 371-388 located in the core coding region of the HCV RNA (Alt M. et al. Archives of Virology 1997, 142, 589 and Galderisi U. et al, Journal of Cellular Physiology 1999, 57:2151);
- Amantadine such as rimantadine (Smith, Abstract from Annual Meeting of the American Gastoenterological Association and AASLD, 1996); 14. Quinolones, such as ofloxacin, ciprofloxacin and levofloxacin (AASLD Abstracts, Hepatology, Oct. 1994, Program Issue, 20 (4), pt.2, abstract no. 293);
- Nucleoside analogs (Ismaili et al. WO 01/60315; Storer WO 01/32153), including 2'-deoxy ⁇ L-nucleosides (Watanabe et al. WO 01/34618), and l-( ⁇ -L- ribofuranosyl)-l,2,4-triazole-3-carboxamide (levovirinTM) (Tarn WO 01/46212); and
- miscellaneous compounds including 1-amino-alkylcyclohexanes (Gold et al. U.S. Patent No. 6,034,134), alkyl lipids (Chojkier et al. U.S. Patent No. 5,922,757), vitamin E and other antioxidants (Chojkier et al. U.S. Patent No. 5,922,757), squalene, bile acids (Ozeki et al. U.S. Patent No. 5,846,964), N- (phosphonoacetyl)-L-aspartic acid, (Diana et al. U.S. Patent No. 5,830,905), benzenedicarboxamides (Diana et al.
- the Orthomyxoviridae is a group of segmented negative single-stranded RNA viruses with a genome size from 10-13.6 kb. They are enveloped viruses of approximately 80-120 nm. An overview of the Orthomyxoviridae taxonomy is available from the International Committee for Taxonomy of Viruses. The Orthomyxoviridae consists of three genera, which can be distinguished on the basis of antigenic differences between their nucleocapsid (NP) and matrix proteins (M).
- NP nucleocapsid
- M matrix proteins
- influenza A Infiuenzavirus A, B. This genus contains influenza A and B viruses each of which contain eight distinct RNA segments. Influenza B viruses show little variability in their surface glycoproteins and only infect humans. On the other hand, influenza A viruses have great variability in their surface glycoproteins of influenza A viruses, and they can be divided into subtypes based on the antigenic nature of their hemagglutinin (HA) and neuroamidase (NA) glycoproteins and infect humans as well as swine, horses, seals, fowl, ducks and many other species of birds.
- HA hemagglutinin
- NA neuroamidase glycoproteins and infect humans
- influenza C This genus contains only one species, influenza C, which contains only seven distinct RNA segments. Influenza C only has a single multifinctional glycoprotein and infects mainly humans, but has also been isolated from swine in China.
- influenza D This genus contains influenza D, which is solely tick-borne viruses that are structurally and genetically similar to influenza A, B and C.
- influenza A virus One of the most important Orthomyxoviridae infections in humans is caused by the influenza A virus. These viruses are highly contagious and cause acute respiratory illness that has plagued society in epidemic proportions since ancient times. One of the earliest recordings of an influenza A epidemic can be traced to Hippocrates in 412 BC. These epidemics are rather frequent and are often fatal to the elderly, however these epidemics are quite unpredictable. These viruses are unique respiratory tract viruses, in that they undergo significant antigenic variation. Both hemagglutinin (HA) and neuroamidase (NA) glycoproteins are capable of antigenic drifts and shifts. There are fourteen known hemagglutinin (HI -HI 4) glycoproteins and nine known neuroamidase (N1-N9) glycoproteins.
- H2N2 subtype Asian influenza
- HlNl subtype Spanish influenza
- influenza A virion The vast majority of research on influenza virus gene expression and RNA replication has been carried out with the influenza A virus.
- the most striking feature of the influenza A virion is a layer of about 500 spikes radiating outward (10 to 14 nm) from the lipid envelope. These spikes are of two types: rod-shaped spikes of HA and mushroom-shaped spikes of NA. The ratio of HA and NA varies, but is usually 4-5 to 1.
- Each gene segment encodes its own proteins, with the exception of the seventh and eighth, which encodes Mi and M 2 , and NSi and NS 2 respectively.
- the first 12 nucleotides at the 3'-end and the first 13 nucleotides at the 5'-end of each vRNA segment are conserved in all eight RNA segments.
- the first gene to have its nucleotide sequence determined was HA. Since then, all 14 known HA antigenic subtypes and many variants within the subtypes have been determined.
- the vRNAs are both transcribed into mRNAs and replicated.
- the synthesis of mRNA is distinct, in that the RNA is primed by 5' capped fragments derived from newly synthesized host-cell RNA polymerase II transcripts.
- the mRNA chain elongates until a stretch of uridine residues is reached 15-22 nucleotides before the 5 '-ends of the vRNAs where transcription ends and polyadenylate is added to the mRNAs.
- an alternative type of transcription is required that results in the production of full-length copies of the vRNAs.
- the full-length transcripts are initiated without a primer and are not terminated at the poly(A) site used during mRNA synthesis.
- the second step in replication is the copying of the template RNAs into vRNAs. This synthesis also occurs without a primer, since the vRNAs contain 5'-triphosphorylated ends. All three types of virus-specific RNAs - mRNA, template RNA and vRNA - are synthesized in the nucleus.
- antiviral agents that have been identified as active against the influenza A virus include:
- the Paramyxoviridae is a group of negative single-stranded RNA viruses with a genome size from 16-20 kb. They are enveloped viruses of approximately 150-300 nm. An overview of the Paramyxoviridae taxonomy is available from the International Committee for Taxonomy of Viruses. The Paramyxoviridae consists of two subfamilies.
- Paramyxovirus This genus is represented by Sendai virus and including human parainfluenza viruses 1 and 3;
- Rubulavirus This genus is represented by the mumps virus, simian virus 5, Newcastle disease virus and the human parainfluenza viruses 2 and 4; c) Morbillivirus. This genus is represented by the measles virus; and
- Pneumovirus This genus is best represented by the respiratory syncytial virus (RSV), but also includes bovine (BRSV), ovine RSV (ORSC), caprine RSV (CRSV), pneumonia virus of mice (PVM) and turkey rhinotracheitis virus (TRTV).
- RSV respiratory syncytial virus
- BRSV bovine
- RSC ovine RSV
- CRSV caprine RSV
- PVM pneumonia virus of mice
- TRTV turkey rhinotracheitis virus
- RSV respiratory syncytial virus
- genomic RSV R ⁇ A The 3 '-end of genomic RSV R ⁇ A consists of a 44-nucleotide extragenic leader region that is presumed to contain the major viral promoter. The leader region is followed by the ten viral genes, which is followed by a 155-nucleotide extragenic trailer region. Eighty eight percent of the genomic R ⁇ A is accounted for by the ORFs for the ten major proteins. Each gene begins with a conserved nine-nucleotide gene-start signal. For each gene, transcription begins at the first nucleotide of the signal. Each gene terminates with a semi-conserved 12 to 13 nucleotide gene-end signal that directs transcriptional termination and polyadenylation.
- the first nine genes are non-overlapping and are separated by intergenic regions that range in size from 1 to 52 nucleotides.
- the intergenic regions do not Gontain any conserved sequence motifs or any obvious features of secondary structure.
- the last two RSV genes overlap by 68 nucleotides. Thus, one of the gene-start signals is located inside of, rather than after the other gene.
- antiviral agents examples include: 1. Ribavirin (Hruska, J. F. et al. "In vivo inhibition of respiratory syncytial virus by ribavirin” Antimicrob Agents Chemother, 1982, 21, 125-130); and
- Cellular differentiation, growth, function and death are regulated by a complex network of mechanisms at the molecular level in a multicellular organism. In the healthy animal or human, these mechanisms allow the cell to carry out its designed function and then die at a programmed rate.
- Abnormal cellular proliferation notably hyperproliferation
- Psoriasis is a benign disease of human skin generally characterized by plaques covered by thickened scales. The disease is caused by increased proliferation of epidermal cells of unknown cause. In normal skin the time required for a cell to move from the basal layer to the upper granular layer is about five weeks. In psoriasis, this time is only 6 to 9 days, partially due to an increase in the number of proliferating cells and an increase in the proportion of cells which are dividing (G. Grove, Int. J. Dermatol. 18:111, 1979).
- Other diseases caused by hyperproliferation of skin cells include atopic dermatitis, lichen planus, warts, pemphigus vulgaris, actinic keratosis, basal cell carcinoma and squamous cell carcinoma.
- Other hyperproliferative cell disorders include blood vessel proliferation disorders, fibrotic disorders, autoimmune disorders, graft- versus-host rejection, tumors and cancers.
- Blood vessel prohferative disorders include angiogenic and vasculogenic disorders.
- Proliferation of smooth muscle cells in the course of development of plaques in vascular tissue cause, for example, restenosis, retinopathies and atherosclerosis.
- the advanced lesions of atherosclerosis result from an excessive inflammatory-proliferative response to an insult to the endothelium and smooth muscle of the artery wall (Ross, R. Nature, 1993, 362:801-809). Both cell migration and cell proliferation play a role in the formation of atherosclerotic lesions.
- Fibrotic disorders are often due to the abnormal formation of an extracellular matrix.
- fibrotic disorders include hepatic cirrhosis and mesangial prohferative cell disorders.
- Hepatic cirrhosis is characterized by the increase in extracellular matrix constituents resulting in the formation of a hepatic scar.
- Hepatic cirrhosis can cause diseases such as cirrhosis of the liver.
- An increased extracellular matrix resulting in a hepatic scar can also be caused by viral infection such as hepatitis. Lipocytes appear to play a major role in hepatic cirrhosis.
- Mesangial disorders are brought about by abnormal proliferation of mesangial cells.
- Mesangial hyperproliferative cell disorders include various human renal diseases, such as glomerulonephritis, diabetic nephropathy, malignant nephrosclerosis, thrombotic micro-angiopathy syndromes, transplant rejection, and glomerulopathies.
- Rheumatoid arthritis is generally considered an autoimmune disease that is thought to be associated with activity of autoreactive T cells (See, e.g., Harris, E. D., Jr., The New England Journal of Medicine, 1990, 322: 1277-1289), and to be caused by autoantibodies produced against collagen and IgE.
- pulmonary embolism Other disorders that can include an abnormal cellular prohferative component include Behcet's syndrome, acute respiratory distress syndrome (ARDS), ischemic heart disease, post-dialysis syndrome, leukemia, acquired immune deficiency syndrome, vasculitis, lipid histiocytosis, septic shock and inflammation in general.
- ARDS acute respiratory distress syndrome
- ischemic heart disease post-dialysis syndrome
- leukemia CAD
- acquired immune deficiency syndrome vasculitis
- vasculitis lipid histiocytosis
- septic shock inflammation in general.
- a tumor also called a neoplasm, is a new growth of tissue in which the multiplication of cells is uncontrolled and progressive.
- a benign tumor is one that lacks the properties of invasion and metastasis and is usually surrounded by a fibrous capsule.
- a malignant tumor i.e., cancer
- Malignant tumors also show a greater degree of anaplasia (i.e., loss of differentiation of cells and of their orientation to one another and to their axial framework) than benign tumors.
- Prohferative disorders are currently treated by a variety of classes of compounds including alkylating agents, antimetabolites, natural products, enzymes, biological response modifiers, miscellaneous agents, radiopharmaceuticals (for example, Y-90 tagged to hormones or antibodies), hormones and antagonists, such as those listed below.
- alkylating agents for example, alkylating agents, antimetabolites, natural products, enzymes, biological response modifiers, miscellaneous agents, radiopharmaceuticals (for example, Y-90 tagged to hormones or antibodies), hormones and antagonists, such as those listed below.
- Nitrogen Mustards Mechlorethamine (Hodgkin's disease, non-Hodgkin's lymphomas), Cyclophosphamide, Ifosfamide (acute and chronic lymphocytic leukemias, Hodgkin's disease, non-Hodgkin's lymphomas, multiple myeloma, neuroblastoma, breast, ovary, lung, Wilms' tumor, cervix, testis, soft-tissue sarcomas), Melphalan (L-sarcolysin) (multiple myeloma, breast, ovary), Chlorambucil (chronic lymphoctic leukemia, primary macroglobulinemia, Hodgkin's disease, non-Hodgkin's lymphomas).
- Ethylenimines and Mefhylmelamines Hexamethylmelamine (ovary), Thiotepa (bladder, breast, ovary).
- Alkyl Sulfonates Busulfan (chronic granuloytic leukemia).
- Nitrosoureas Carmustine (BCNU) (Hodgkin's disease, non-Hodgkin's lymphomas, primary brain tumors, multiple myeloma, malignant melanoma), Lomustine (CCNU) (Hodgkin's disease, non-Hodgkin's lymphomas, primary brain tumors, small-cell lung), Semustine (methyl-CCNU) (primary brain tumors, stomach, colon), Streptozocin (STR) (malignant pancreatic insulinoma, malignant carcinoin).
- Triazenes dacarbazine (DTIC; dimethyltriazenoimidazole-carboxamide) (malignant melanoma, Hodgkin's disease, soft-tissue sarcomas).
- Methotrexate (amethopterin) (acute lymphocytic leukemia, choriocarcinoma, mycosis fungoides, breast, head and neck, lung, osteogenic sarcoma).
- Fluorouracil (5-fiuorouracil; 5-FU) Floxuridine (fluorodeoxyuridine; FUdR) (breast, colon, stomach, pancreas, ovary, head and neck, urinary bladder, premalignant skin lesions) (topical), Cytarabine (cytosine arabinoside) (acute granulocytic and acute lymphocytic leukemias).
- Mercaptopurine (6-mercaptopurine; 6-MP) (acute lymphocytic, acute granulocytic and chronic granulocytic leukemia), Thioguanine (6-thioguanine: TG) (acute granulocytic, acute lymphocytic and chronic granulocytic leukemia), Pentostatin (2'-deoxycyoformycin) (hairy cell leukemia, mycosis fungoides, chronic lymphocytic leukemia).
- 6-MP acute lymphocytic, acute granulocytic and chronic granulocytic leukemia
- Thioguanine (6-thioguanine: TG) (acute granulocytic, acute lymphocytic and chronic granulocytic leukemia)
- Pentostatin (2'-deoxycyoformycin) (hairy cell leukemia, mycosis fungoides, chronic lymphocytic leukemia).
- Vinca Alkaloids Vinblastine (VLB) (Hodgkin's disease, non-Hodgkin's lymphomas, breast, testis), Vincristine (acute lymphocytic leukemia, neuroblastoma, Wilms' tumor, rhabdomyosarcoma, Hodgkin's disease, non-Hodgkin's lymphomas, small- cell lung).
- VLB Vinblastine
- Vincristine acute lymphocytic leukemia, neuroblastoma, Wilms' tumor, rhabdomyosarcoma
- Hodgkin's disease non-Hodgkin's lymphomas, small- cell lung.
- Epipodophylotoxins Etoposide (testis, small-cell lung and other lung, breast, Hodgkin's disease, non-Hodgkin's lymphomas, acute granulocytic leukemia, Kaposi's sarcoma), Teniposide (testis, small-cell lung and other lung, breast, Hodgkin's disease, non-Hodgkin's lymphomas, acute granulocytic leukemia, Kaposi's sarcoma).
- Dactinomycin actinonmycin D
- choriocarcinoma choriocarcinoma, Wilms' tumor rhabdomyosarcoma, testis, Kaposi's sarcoma
- DaunorubiGin daunomycin; rubidomycin
- Doxorubicin soft tissue, osteogenic, and other sarcomas
- Hodgkin's disease non-Hodgkin's lymphomas, acute leukemias, breast, genitourinary thyroid, lung, stomach, neuroblastoma
- Bleomycin testis, head and neck, skin and esophagus lung, and genitourinary tract
- Hodgkin's disease non-Hodgkin's lymphomas
- Plicamycin mithramycin
- Mitomycin mitomycin C
- Enzymes L-Asparaginase (acute lymphocytic leukemia).
- Interferon-alfa hairy cell leukemia, Kaposi's sarcoma, melanoma, carcinoid, renal cell, ovary, bladder, non Hodgkin's lymphomas, mycosis fungoides, multiple myeloma, chronic granulocytic leukemia).
- Cisplatin cis-DDP
- Carboplatin testis, ovary, bladder, head and neck, lung, thyroid, cervix, endometrium, neuroblastoma, osteogenic sarcoma).
- Anthracenedione Mixtozantrone (acute granulocytic leukemia, breast).
- Substituted Urea Hydroxyurea (chronic granulocytic leukemia, polycyfhemia vera, essential thrombocytosis, malignant melanoma).
- Methylhydrazine Derivative Procarbazine (N-methylhydrazine, MIH) (Hodgkin's disease).
- Mitotane o,p'-DDD
- Amino- glutethimide breast
- Adrenorticosteriods Prednisone (acute and chronic lymphocytic leukemias, non- Hodgkin's lymphomas, Hodgkin's disease, breast).
- Progestins Hydroxprogesterone caproate, Medroxyprogesterone acetate, Megestrol acetate (endometrium, breast).
- Estrogens Diethylstibestrol Ethinyl estradiol (breast, prostate)
- Antiestrogen Tamoxifen (breast).
- Androgens Testosterone propionate Fluxomyesterone (breast). Antiandrogen: Flutamide (prostate).
- Toxicity associated with therapy for abnormally proliferating cells, including cancer, is due in part to a lack of selectivity of the drug for diseased versus normal cells.
- therapeutic strategies that increase the specificity and thus reduce the toxicity of drugs for the treatment of prohferative disorders are being explored.
- One such strategy that is being aggressively pursued is drug targeting.
- the present invention provides a ⁇ -D or ⁇ -L nucleoside of formula (I) - (XXIII) or its pharmaceutically acceptable salt or prodrug for the treatment of a host infected with a virus belonging to the Flaviviridae, Orthomyxoviridae and Paramyxoviridae family.
- the ⁇ -D or ⁇ -L nucleoside (I) - (XXIII) or its pharmaceutically acceptable salt or prodrug can be used for the treatment of abnormal cellular proliferation.
- the invention also includes methods for treating or preventing the following:
- a Flaviviridae infection including all members of the Hepacivirus genus (HCV), Pestivirus genus (BVDV, CSFV, BDV), or Flavivirus genus (Dengue virus, Japanese encephalitis virus group (including West Nile Virus), and Yellow Fever virus);
- HCV Hepacivirus genus
- BVDV Pestivirus genus
- CSFV Pestivirus genus
- BDV Flavivirus genus
- Flavivirus genus Dengue virus, Japanese encephalitis virus group (including West Nile Virus), and Yellow Fever virus
- the anti-virally or anti-proliferatively effective nucleoside is a ⁇ -D nucleoside ofthe general formula (I) or (II):
- each D is hydrogen, alkyl, acyl, monophosphate, diphosphate, triphosphate, monophosphate ester, diphosphate ester, triphosphate ester, phospholipid or amino acid;
- each W 1 and W 2 is independently CH or N;
- each X 1 and X 2 is independently hydrogen, halogen (F, Cl, Br or I), NH 2 , NHR 4 , NR-V, NHOR 4 , NR 4 NR 4' R 4" , OH, OR 4 , SH or SR 4 ;
- each Y 1 is O, S or Se
- each Z is CH 2 or NH; each R 1 and R 1 is independently hydrogen, lower alkyl, lower alkenyl, lower alkynyl, aryl, alkylaryl, halogen (F, Cl, Br or I), NH 2 , NHR 5 , NR 5 R 5' , NHOR 5 , NR 5 NHR 5' , NR 5 NR 5 5" , OH, OR 5 , SH, SR 5 , NO 2 , NO, CH 2 OH, CH 2 OR 5 , CO 2 H, CO 2 R 5 , CONH 2 , CONHR 5 , CONR 5 R 5' or CN;
- each R 4 , R 4 , R 4 , R 5 , R 5 and R 5 independently is hydrogen, lower alkyl, lower alkenyl, aryl, or arylalkyl such as unsubstituted or substituted phenyl or benzyl;
- anti-virally or anti-proliferatively effective nucleoside is a ⁇ -L nucleoside ofthe general formula (III) or (IV):
- each D, W 1 , W 2 , X 1 , X 2 , Y 1 , Z, R 1 , R 1 ' , R 2 , R 2' , R 3 and R 3' is the same as defined previously;
- the anti-virally or anti-proliferatively effective nucleoside is a ⁇ -D-carba-sugar nucleoside ofthe general formula (V) to (VII):
- each D, W 1 , W 2 , X 1 , X 2 , Y 1 , Z, R 1 , R 1 ' , R 2 , R 2' , R 3 and R 3> is the same as defined previously; ' such that for each nucleoside of the general formula (V) or (VI), at least one of R and R is hydrogen and at least one of R and R is hydrogen.
- anti-virally or anti-proliferatively effective nucleoside is a ⁇ - L-carba-sugar nucleoside of the general formula (VIII) to (X):
- each D, W 1 , W 2 , X 1 , X 2 , Y 1 , Z, R 1 , R 1 ' , R 2 , R 2' , R 3 and R 3' is the same as defined previously;
- the anti-virally or anti-proliferatively effective ⁇ -D or ⁇ -L-nucleoside is of the general formula (XI) or (XII), respectively:
- each D, W 1 , W 2 , X 1 , X 2 , Y 1 , Z, R 1 , R 1' , R 2 , R 2' , R 3 and R 3' is the same as defined previously;
- each Z 1 and Z 2 independently is O, S, CH 2 , NR 6 or Se;
- each R 6 is hydrogen, lower alkyl or lower acyl.
- the anti-virally or anti-proliferatively effective ⁇ -D or ⁇ -L-nucleoside is of the general formula (XIII):
- each D, R ! , R 1 , R 2 , R 2 , R 3 and R 3 is the same as defined previously;
- each Y 2 is O, S, NH or NR 7 ;
- each Y 3 is O, S, NH or NR 8 ;
- each X 3 is OR 9 or SR 9 ;
- each R , R and R is hydrogen, lower alkyl of C ⁇ -C 6 , arylalkyl or aryl;
- the anti-virally or anti-proliferatively effective compound is a ⁇ -D or ⁇ -L-nucleoside, though preferably ⁇ -D, resulting from the addition of a small molecule, such as alkyl hypochlorite, alkyl hypobromite, hypobromous acid or acyl halide to an appropriate pyrimidine nucleoside, forming a nucleoside ofthe formula (XIV):
- each D, X 1 , Y 1 , Z 1 , R 1 , R 2 , R 2' , R 3 and R 3' is the same as defined previously;
- each L 1 is hydrogen, Cl or Br
- each L 2 is OH, OCH 3 , OC 2 H 5 , OC 3 H7, OCF 3 , OAc or OBz;
- each Z 3 can be O or CH 2 .
- the anti-virally or anti-proliferatively effective nucleoside is a dimeric nucleoside (each nucleoside being in either the ⁇ -D or ⁇ -L configuration) of general formula (XV), in which the two nucleosides are linked through a disulfide bond:
- each D, W 1 , W z , X 1 , Y 1 , Z R ⁇ R' , R , R z , R J and R J is the same as defined previously.
- the anti-virally or anti-proliferatively effective nucleoside is a ⁇ -D or ⁇ -L C-nucleoside ofthe general formula (XVI):
- each D, W 1 , X 1 , X 2 , Y 1 , Z, R 1 , R 2 , R 2' , R 3 and R 3' is the same as defined previously;
- each W 3 is independently N, CH or CR 1 ;
- each W 4 and W 5 is independently N, CH, CX 1 or CR 1 ' ;
- the anti-virally or anti-proliferatively effective nucleoside is a ⁇ -D or ⁇ -L-branched-chain sugar nucleoside of the general formula (XVII):
- each D, W 1 , W 2 , X 1 , X 2 , Y 1 , Z 3 , R 1 , R 1' , R 2 , R 2* , R 3 and R 3' is the same as defined previously; each X 4 and X 5 is independently hydrogen, halogen (F, Cl, Br or I), N 3 , NH 2 , NHR 8 , NR 8 R 8> , OH, OR 8 , SH or SR 8 ; and
- each R 8 and R 8 is independently hydrogen, lower alkyl, lower alkenyl, aryl or arylalkyl, such as an unsubstituted or substituted phenyl or benzyl;
- the anti-virally or anti-proliferatively effective nucleoside is a ot ⁇ D or ⁇ -L-nucleoside of the general formula (XVIII):
- each D, W 1 , W 2 , X 1 , X 2 , Y 1 , R 1 , R 1 ' , R 2 , R 2' , R 3 and R 3' is the same as defined previously;
- the anti-virally or anti- proliferatively effective ⁇ -D or ⁇ -L nucleoside is ofthe formula (XIX):
- each D, R 1 , R and R 4 is the same as defined previously;
- each R 9 is hydrogen, halogen (F, Cl, Br or I) or OP 3 ;
- each P 1 is hydrogen, lower alkyl, lower alkenyl, aryl, arylalkyl (such as an unsubstituted or substituted phenyl or benzyl), OH, OR 4 , NH 2 , NHR 4 or NR 4 R 4' ; and
- each P 2 and P 3 is independently hydrogen, alkyl, acyl, -Ms, -Ts, monophosphate, diphosphate, triphosphate, mono-phosphate ester, diphosphate ester, triphosphate ester, phospholipid or amino acid, though preferably hydrogen.
- the anti-virally or anti- proliferatively effective ⁇ -D or ⁇ -L nucleoside of the formula (XIX) is the following:
- each D and P 2 is the same as defined previously.
- D and P 2 are independently hydrogen.
- the anti-virally or anti- proliferatively effective ⁇ -D or ⁇ -L nucleoside is ofthe formula (XX):
- each D, P , P , P , P , R , R .4' and R 9 is. the same as defined previously.
- the anti-virally or anti- proliferatively effective ⁇ -D or ⁇ -L nucleoside is ofthe formula (XXI):
- each D, P 1 , P 2 , P 3 , R 1 , R 4 and R 4 is the same as defined previously.
- the anti-virally or anti- proliferatively effective ⁇ -D or ⁇ -L nucleoside of the formula (XXI) is the following:
- each D, P 2 and P 3 is the same as defined previously.
- D, P 2 and P 3 are independently hydrogen.
- the anti-virally or anti- proliferatively effective ⁇ -D or ⁇ -L nucleoside is of the formula (XXII):
- each D, P 1 and R 1 is the same as defined previously.
- D and P 2 are independently hydrogen.
- the anti-virally or anti- proliferatively effective ⁇ -D or ⁇ -L nucleoside, though preferably ⁇ -L, of the formula (XXII) is the following:
- D is the same as defined previously, and preferably H.
- the anti-virally or anti- proliferatively effective ⁇ -D or ⁇ -L nucleoside is ofthe formula (XXIII):
- each D, P 1 , P 2 , P 3 , R l , R 4 and R 4 is the same as defined previously.
- the anti-virally or anti- proliferatively effective ⁇ -D or ⁇ -L nucleoside o the formula (XXIII) is the following:
- P -.3 are independently hydrogen.
- the nucleoside has an EC 50 (effective concentration to achieve 50% viral inhibition) when tested in an appropriate cell-based assay, of less than 15 mioromolar, and more particularly, less than 10 or 5 micromolar. In a preferred embodiment, the nucleoside is enantiomerically enriched.
- the present invention also includes at least the following features:
- a pharmaceutical composition that include an antivirally effective amount of a ⁇ -D nucleoside or ⁇ -L nucleoside of formula (I) - (XXIII), as described herein, or its pharmaceutically acceptable salt or prodrug thereof together with a pharmaceutically acceptable carrier or diluent according to the present invention;
- a pharmaceutical composition with a ⁇ -D nucleoside or ⁇ -L nucleoside of formula (I) - (XXIII), as described herein, or its pharmaceutically acceptable salt or prodrug thereof in combination with one or more other antivirally effective agents and
- RT-PCR real-time polymerase chain reaction
- a probe molecule with a sequence of 5'-6-fam-CCTCCAGGACCCCCCCTCCC- tamara-3' (Sequence ID No 4) and primers with a sequence of sense: 5'-AGCCATGGCGTTAGTA(T/C)GAGTGT-3' (Sequence ID No 5) and antisense: 5'-TTCCGCAGACCACTATGG-3' (Sequence ID No 6).
- Figure 1 is an illustration of the increase in plaque forming units with increasing concentration of bovine viral diarrhea virus ("BVDV”) in cell culture as described in Example 51.
- Figure 1 establishes that the method of Example 51 provides reliable quantification of BVDV over a four log PFU/mL of virus.
- BVDV bovine viral diarrhea virus
- Figure 2 is an illustration of the BVDV replication cycle in MDBK cells to determine the optimal harvesting time (in hours post infection versus the log of plaque forming units ("PFU"), i.e. 22 hours after infection, which roughly corresponds to approximately one replication cycle, where the amount of virus produced is equal to the amount of virus inoculated into the cell, as described in Example 52.
- PFU plaque forming units
- Figure 3 is a bar chart graph showing the ability of certain test compounds to inhibit the number of plaque forming units, as described in Example 40 against BVDV.
- Figure 4 is a line graph illustrating that the prevention of cytotoxicity of a "carba- sugar" nucleoside in CEM cells (human T-cell lymphoma) and in SUDHL-l cells (human anaplastic T-cell lymphoma cell line) can be accomplished by co-administration of natural nudeosides, namely cytidine and uridine. 46113
- Figure 5 provides the structure of various non-limiting examples of nucleosides of the present invention, as well as the known nucleoside, ribavirin, which is used as a comparative example in the text.
- the present invention provides a nucleoside of the general formula (I) - (XXIII) or its pharmaceutically acceptable salt or prodrug for the treatment of a host infected with a virus belonging to the Flaviviridae, the Orthomyxoviridae, or the Paramyxoviridae family.
- the nucleoside of the general formula (I) - (XXIII) or its pharmaceutically acceptable salt or prodrug can be used for the treatment of abnormal cellular proliferation.
- a method for the treatment or prophylaxis of an antiviral or antiproliferative agent for example for the treatment or prophylaxis of a viral infections, including Flaviviridae infections, including hepatitis C infection, influenza virus infection, including influenza A (such as HlNl and H3N2) and influenza B and RSV, as well as abnormal cellular proliferation that includes the administration of an anti-virally or anti- proliferatively effective amount of a nucleoside of the present invention, or its pharmaceutically acceptable salt or prodrug thereof is provided.
- a viral infections including Flaviviridae infections, including hepatitis C infection, influenza virus infection, including influenza A (such as HlNl and H3N2) and influenza B and RSV, as well as abnormal cellular proliferation that includes the administration of an anti-virally or anti- proliferatively effective amount of a nucleoside of the present invention, or its pharmaceutically acceptable salt or prodrug thereof.
- a method for the treatment or prophylaxis of an antiviral or antiproliferative agent for example for the treatment or prophylaxis of a Flaviviridae infection that includes the administration of an antivirally amount of a nucleoside of the present invention, or its pharmaceutically acceptable salt or prodrug thereof in the manufacture of a medicament for treatment is provided.
- a method for the treatment or prophylaxis of an antiviral or antiproliferative agent for example for the treatment or prophylaxis of an Influenza virus infection that includes the administration of an antivirally effective amount of a nucleoside of the present invention, or its pharmaceutically acceptable salt or prodrug thereof in the manufacture of a medicament for treatment is provided.
- a method for the treatment or prophylaxis of an antiviral or antiproliferative agent for example for the treatment or prophylaxis of a RSV infection that includes the administration of an antivirally effective amount of the present invention, or its pharmaceutically acceptable salt or prodrug thereof in the manufacture of a medicament for treatment is provided.
- a method for the treatment or prophylaxis of an antiviral or antiproliferative agent for example for the treatment or prophylaxis of a disease characterized by abnormal cellular proliferation that includes the administration of an anti- proliferatively effective amount of a nucleoside ofthe present invention.
- the invention is the use of one ofthe compounds described herein in the manufacture of a medicament for the treatment of a viral infection or abnormal cellular proliferation, as provided herein.
- the invention is the use of one ofthe compounds described herein in the treatment of a host exhibiting a viral infection or abnormal cellular proliferation, as provided herein.
- a pharmaceutical composition that includes an antivirally or anti-proliferatively effective amount of a nucleoside of the present invention, or its pharmaceutically acceptable salt or prodrug thereof together with a pharmaceutically acceptable carrier or diluent according to the present invention is provided.
- a pharmaceutical composition with a nucleoside of the present invention, or its pharmaceutically acceptable salt or prodrug thereof in combination with one or more other antivirally or anti-proliferatively effective agents is provided.
- nucleosides of the present invention in another embodiment, a process for the preparation of the nucleosides of the present invention, and its pharmaceutically acceptable salt and prodrug thereof is provided.
- a method of treating a mammal having a virus- associated disorder which comprises administering to the mammal a pharmaceutically effective amount of a nucleoside of the present invention, or their pharmaceutically acceptable salts or prodrugs thereof, is provided.
- a method of treating a mammal having disorder associated with abnormal cellular proliferation which comprises administering to the mammal a pharmaceutically effective amount of a nucleoside of the present invention, or their pharmaceutically acceptable salts or prodrugs thereof, is provided.
- the invention includes the described compounds in methods for treating or preventing, or uses for the treatment or prophylaxis of, or uses in the manufacture of a medicament for following:
- a Flaviviridae infection including all members of the Hepacivirus genus (HCV), Pestivirus genus (BVDV, CSFV, BDV), or Flavivirus genus (Dengue virus, Japanese encephalitis virus group (including West Nile Virus), and Yellow Fever virus);
- HCV Hepacivirus genus
- BVDV Pestivirus genus
- CSFV Pestivirus genus
- BDV Flavivirus genus
- Flavivirus genus Dengue virus, Japanese encephalitis virus group (including West Nile Virus), and Yellow Fever virus
- a Paramyxoviridae infection including Respiratory Syncytial Virus (RSV) infection
- RSV Respiratory Syncytial Virus
- the anti-virally or anti-proliferatively effective nucleoside is a ⁇ -D nucleoside ofthe general formula (I) or (II):
- each D is hydrogen, alkyl, acyl, monophosphate, diphosphate, triphosphate, monophosphate ester, diphosphate ester, triphosphate ester, phospholipid or amino acid, though preferably hydrogen;
- each W and W is independently CH or N;
- each X 1 and X 2 is independently hydrogen, halogen (F, Cl, Br or I), NH 2 , NHR 4 , NR 4 R 4' , NHOR 4 , NR 4 NR 4' R 4" , OH, OR 4 , SH or SR 4 ;
- each Y 1 is O, S or Se
- each Z is CH or NH
- each R 1 and R 1 is independently hydrogen, lower alkyl, lower alkenyl, lower alkynyl, aryl, alkylaryl, halogen (F, Cl, Br or I), NH 2 , NHR 5 , NR 5 R 5' , NHOR 5 , NR 5 NHR 5' , NR 5 NR 5> R 5" , OH, OR 5 , SH, SR 5 , NO 2 , NO, CH 2 OH, CH 2 OR 5 , CO 2 H, CO 2 R 5 , CONH 2 , CONHR 5 , CONR 5 R 5' or CN;
- each R 4 , R 4 , R 4 , R 5 , R 5 and R 5 independently is hydrogen, lower alkyl, lower alkenyl, aryl, or arylalkyl such as unsubstituted or substituted phenyl or benzyl;
- anti-virally or anti-proliferatively effective nucleoside is a ⁇ -L nucleoside ofthe general formula (III) or (IV):
- each D, W 1 , W 2 , X 1 , X 2 , Y 1 , Z, R 1 , R r , R 2 , R 2' , R 3 and R 3' is the same as defined previously;
- the anti-virally or anti-proliferatively effective nucleoside is a ⁇ -D-carba-sugar nucleoside ofthe general formula (V) to (VII):
- each D, W 1 , W 2 , X 1 , X 2 , Y 1 , Z, R 1 , R , R 2 , R 2' , R 3 and R 3' is the same as defined previously;
- anti-virally or anti-proliferatively effective nucleoside is a ⁇ - L-carba-sugar nucleoside ofthe general formula (VIII) to (X):
- each D, W 1 , W 2 , X 1 , X 2 , Y 1 , Z, R 1 , R 1 ' , R 2 , R 2' , R 3 and R 3' is the same as defined previously;
- the anti-virally or anti-proliferatively effective ⁇ -D or ⁇ -L-nucleoside is of the general formula (XI) or (XII), respectively:
- each D, W 1 , W 2 , X 1 , X 2 , Y 1 , Z, R 1 , R r , R 2 , R 2' , R 3 and R 3' is the same as defined previously;
- each Z 1 and Z 2 independently is O, S, NR 6 or Se;
- each R 6 is hydrogen, lower alkyl or lower acyl.
- the anti-virally or anti-proliferatively effective ⁇ -D or ⁇ -L-nucleoside is of the general formula (XIII):
- each D, R 1 , R 1 , R 2 , R 2 , R 3 and R 3 is the same as defined previously;
- each Y 2 is O, S, NH or NR 7 ;
- each Y 3 is O, S, NH or NR 8 ;
- each X 3 is OR 9 or SR 9 ;
- each R , R and R is hydrogen, lower alkyl of C]-C 6 , arylalkyl or aryl;
- the anti-virally or anti-proliferatively effective is a ⁇ -D or ⁇ -L-nucleoside, though preferably ⁇ -D, resulting from the addition of a small molecule, such as alkyl hypochlorite, alkyl hypobromite, hypobromous acid or acyl halide to an appropriate pyrimidine nucleoside, forming a nucleoside o the formula (XIV):
- each D, X 1 , Y 1 , Z 1 , R 1 , R 2 , R 2' , R 3 and R 3' is the same as defined previously;
- each L 1 is hydrogen, Cl or Br
- each L 2 is OH, OCH 3 , OC 2 H 5 , OC 3 H 7 , OCF 3 , OAc or OBz;
- each Z 3 can be O or CH 2 .
- the anti-virally or anti-proliferatively effective nucleoside is a dimeric nucleoside (each nucleoside being in either the ⁇ -D or ⁇ -L configuration) of general formula (XV), in which the two nucleosides are linked through a disulfide bond:
- each D, W 1 , W 2 , X 1 , Y 1 , Z 3 , R 1 , R 1 ' , R 2 , R 2' , R 3 and R 3' is the same as defined previously.
- the anti-virally or anti-proliferatively effective nucleoside is a ⁇ -D or ⁇ -L C-nucleoside of the general formula (XVI):
- each D, W, Y 1 , Z, R , R l , R , R J and R J is the same as defined previously;
- each W 3 is independently N, CH or CR 1 ;
- each W 4 and W 5 is independently N, CH, CX 1 or CR 1 ' ;
- the anti-virally or anti-proliferatively effective nucleoside is a ⁇ -D or ⁇ -L-branched-chain sugar nucleoside ofthe general formula (XVII):
- each D, W 1 , W 2 , X 1 , X 2 , Y 1 , Z 3 , R 1 , R 1 ' , R 2 , R 2' , R 3 and R 3' is the same as defined previously; each X 4 and X 5 is independently hydrogen, halogen (F, Cl, Br or I), N 3 , NH 2 , NHR 8 , NR 8 R 8' , OH, OR 8 , SH or SR 8 ; and
- each R 8 and R 8 is independently hydrogen, lower alkyl, lower alkenyl, aryl or arylalkyl, such as an unsubstituted or substituted phenyl or benzyl;
- X 4 is not OH or OR 8 .
- the anti-virally or anti-proliferatively effective nucleoside is a ⁇ -D or ⁇ -L-nucleoside ofthe general formula (XVIII):
- each D, W 1 , W 2 , X 1 , X 2 , Y 1 , R 1 , R 1 ' , R 2 , R 2' , R 3 and R 3' is the same as defined previously;
- the anti-virally or anti- proliferatively effective ⁇ -D or ⁇ -L nucleoside is of the formula (XIX):
- each D, R 1 , R 4 and R 4 is the same as defined previously;
- each R 9 is hydrogen, halogen (F, Cl, Br or I) or OP 3 ;
- each P 1 is hydrogen, lower alkyl, lower alkenyl, aryl, arylalkyl (such as an unsubstituted or substituted phenyl or benzyl), OH, OR 4 , NH , NHR 4 or NR 4 R 4' ; and
- each P 2 and P 3 is independently hydrogen, alkyl, acyl, -Ms, -Ts, monophosphate, diphosphate, triphosphate, mono-phosphate ester, diphosphate ester, triphosphate ester, phospholipid or amino acid, though preferably hydrogen.
- the anti-virally or anti- proliferatively effective ⁇ -D or ⁇ -L nucleoside ofthe formula (XIX) is the following:
- each D and P 2 is the same as defined previously.
- D and P 2 are independently hydrogen.
- the anti-virally or anti- proliferatively effective ⁇ -D or ⁇ -L nucleoside is ofthe formula (XX):
- each D, P 1 , P 2 , P 3 , R 1 , R , R and R 9 is the same as defined previously.
- the anti-virally or anti- proliferatively effective ⁇ -D or ⁇ -L nucleoside is ofthe formula (XXI):
- each D, P 1 , P 2 , P 3 , R 1 , R 4 and R 4 is the same as defined previously.
- the anti-virally or anti- proliferatively effective ⁇ -D or ⁇ -L nucleoside of the formula (XXI) is the following:
- each D, P 2 and P 3 is the same as defined previously.
- D, P 2 and P 3 are independently hydrogen.
- N-hydroxycytosine is used as the base attached to any of the sugar or carba-sugar moieties described in this application, as if each were fully described a separate specific embodiment.
- the anti-virally or anti- proliferatively effective ⁇ -D or ⁇ -L nucleoside is ofthe formula (XXII):
- each D, P 1 and R 1 is the same as defined previously.
- D and P 2 are independently hydrogen.
- the anti-virally or anti- proliferatively effective ⁇ -D or ⁇ -L nucleoside, though preferably ⁇ -L, of the formula (XXII) is the following:
- D is the same as defined previously, and preferably H.
- the anti-virally or anti- proliferatively effective ⁇ -D or ⁇ -L nucleoside is ofthe formula (XXIII):
- each D, P 1 , P 2 , P 3 , R 1 , R 4 and R 4' is the same as defined previously.
- the anti-virally or anti- proliferatively effective ⁇ -D or ⁇ -L nucleoside o the formula (XXIII) is the following:
- each D, P 2 and P 3 is the same as defined previously.
- D, P 2 and P 3 are independently hydrogen.
- ⁇ -D and ⁇ -L nucleosides of general formula ( ⁇ -a) and (III- a) are represented by the non-limiting examples provided in Table 1.
- ⁇ -D and ⁇ -L nucleosides of general formula (I-b) and (III-b) are represented by the non-limiting examples provided in Table 2.
- ⁇ -D and ⁇ -L nucleosides of general formula (Il-a) and (IV-a) are represented by the non-limiting examples provided in Table 3.
- ⁇ -D and ⁇ -L nucleosides of general formula (Il-b) and (IV-b) are represented by the non-limiting examples provided in Table 4.
- ⁇ -D and ⁇ -L nucleosides of general formula (V-a) and (VHI-a) are represented by the non-limiting examples provided in Table 5.
- ⁇ -D and ⁇ -L nucleosides of general formula (VII- and (X-a) are represented by the non-limiting examples provided in Table 6.
- ⁇ -D and ⁇ -L nucleosides of general formula (VII- b) and (X-b) are represented by the non-limiting examples provided in Table 7.
- ⁇ -D or ⁇ -L nucleosides of general formula (Xl-a) or (Xll-a) are represented by the non-limiting examples provided in Table 8.
- ⁇ -L nucleosides of general formula (Xll-b) are represented by the non-limiting examples provided in Table 9.
- ⁇ -D nucleosides of general formula (Xlll-a) are represented by the non-limiting examples provided in Table 10.
- ⁇ -D nucleosides of general formula (XIII-c) are represented by the non-limiting examples provided in Table 11.
- ⁇ -D nucleosides of general formula (Xlll-d) are represented by the non-limiting examples provided in Table 12.
- ⁇ -D nucleosides of general formula (XIV) are represented by the non-limiting examples provided in Table 13.
- nucleosides of general formula (XV-a) are represented by the non-limiting examples provided in Table 14.
- nucleosides of general formula (XV-b) are represented by the non-limiting examples provided in Table 15.
- nucleosides of general formula (XVI-a) are represented by the non-limiting examples provided in Table 16.
- nucleosides of general formula (XVI-c) are represented by the non-limiting examples provided in Table 17.
- nucleosides of general formula (XVI-d) are represented by the non-limiting examples provided in Table 18.
- nucleosides of general formula (XVI-f) are represented by the non-limiting examples provided in Table 19.
- nucleosides of general formula (XVII-d) are represented by the non-limiting examples provided in Table 20.
- the nucleoside has an EC 50 (effective concentration to achieve 50% viral inhibition) when tested in an appropriate cell-based assay, of less than 15 micromolar, and more particularly, less than 10 or 5 micromolar. In a preferred embodiment, the nucleoside is enantiomerically enriched.
- optically active and racemic forms may exist in and be isolated in optically active and racemic forms. Some compounds may exhibit polymorphism.
- the present invention encompasses racemic, optically-active, polymorphic, or stereoisomeric form, or mixtures thereof, of a compound o the invention, which possess the useful properties described herein.
- the optically active forms can be prepared by, for example, resolution of the racemic form by recrystallization techniques, by synthesis from optically-active starting materials, by chiral synthesis, or by chromatographic separation using a chiral stationary phase or by enzymatic resolution.
- a nucleoside contains at least two critical chiral carbon atoms (*).
- the substituents on the chiral carbons [the specified purine or pyrimidine base (referred to as the Cl substituent when using the sugar ring intermediate numbering) and CH 2 OH (referred to as the C4 substituent)] of the nucleoside can be either cis (on the same side) or trans (on opposite sides) with respect to the sugar ring system. Both the cis and trans racemates consist of a pair of optical isomers. Hence, each compound has four individual stereoisomers.
- the four stereoisomers are represented by the following configurations (when orienting the sugar moiety in a horizontal plane such that the -O- moiety is in back): (1) cis, with both groups "up”, which is referred to as ⁇ -D; (2) the mirror image, i.e., cis, with both groups "down", which is the mirror image is referred to as ⁇ -L; (3) trans with the C4 substituent "up” and the Cl substituent "down” (referred to as ⁇ -D); and (4) trans with the C4 substituent "down” and the Cl substituent "up” (referred to as ⁇ -L).
- the two cis enantiomers together are referred to as a racemic mixture of ⁇ -enantiomers, and the two trans enantiomers are referred to as a racemic mixture of ⁇ - enantiomers.
- alkyl refers to a saturated straight, branched, or cyclic, primary, secondary, or tertiary hydrocarbon, including but not limited to those of Ci to C ⁇ 6 , and specifically includes methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, isobutyl, t-butyl, pentyl, cyclopentyl, isopentyl, neopentyl, hexyl, isohexyl, cyclohexyl, cyclohexylmethyl, 3-methylpentyl, 2,2-dimethylbutyl, and 2,3- dimethylbutyl.
- the alkyl group can be optionally substituted with one or more moieties selected from the group consisting of alkyl, halo, haloalkyl, hydroxyl, carboxyl, acyl, acyloxy, amino, amido, carboxyl derivatives, alkylamino, dialkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, azido, thiol, imine, sulfonic acid, sulfate, sulfonyl, sulfanyl, sulfinyl, sulfamonyl, ester, carboxylic acid, amide, phosphonyl, phosphinyl, phosphoryl, phosphine, thioester, thioether, acid halide, anhydride, oxime, hydrozine, carbamate, phosphonic acid, phosphate, phosphonate, or any other viable functional group that does not inhibit the pharmacological activity
- lower alkyl refers to a Ci to C saturated straight, branched, or if appropriate, a cyclic (for example, cyclopropyl) alkyl group, including both substituted and unsubstituted forms.
- alkylene or "alkenyl” refers to a saturated hydrocarbyldiyl radical of straight or branched configuration, including but not limited to those that have from one to ten carbon atoms. Included within the scope of this term are methylene, 1,2-ethane-diyl, 1,1-ethane-diyl, 1,3-propane-diyl, 1,2-propane-diyl, 1,3-butane-diyl, 1 ,4-butane-diyl and the like.
- alkylene group or other divalent moiety disclosed herein can be optionally substituted with one or more moieties selected from the group consisting of alkyl, halo, haloalkyl, hydroxyl, carboxyl, acyl, acyloxy, amino, amido, carboxyl derivatives, alkylamino, azido, dialkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, thiol, imine, sulfonyl, sulfanyl, sulfinyl, sulfamonyl, ester, carboxylic acid, amide, phosphonyl, phosphinyl, phosphoryl, phosphine, thioester, thioether, acid halide, anhydride, oxime, hydrozine, carbamate, phosphonic acid, phosphonate, or any other viable functional group that does not inhibit the pharmacological activity of this
- aryl refers to phenyl, biphenyl, or naphthyl, and preferably phenyl.
- the term includes both substituted and unsubstituted moieties.
- the aryl group can be substituted with one or more moieties selected from the group consisting of bromo, chloro, fluoro, iodo, hydroxyl, azido, amino, alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate, or phosphonate, either unprotected, or protected as necessary, as known to those skilled in the art, for example, as taught in Greene, et al, Protective Groups in Organic Synthesis, John Wiley and Sons, Second Edition, 1991.
- alkyl refers to an aryl group as defined above linked to the molecule through an alkyl group as defined above.
- alkaryl or “alkylaryl” as used herein, and unless otherwise specified, refers to an alkyl group as defined above linked to the molecule through an aryl group as defined above.
- the alkyl group can be optionally substituted as describe above and the aryl group can be optionally substituted with one or more moieties selected from the group consisting of alkyl, halo, haloalkyl, hydroxyl, carboxyl, acyl, acyloxy, amino, amido, azido, carboxyl derivatives, alkylamino, dialkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, thiol, imine, sulfonyl, sulfanyl, sulfinyl, sulfamonyl, ester, carboxylic acid, amide, phosphonyl, phosphinyl, phosphoryl, phosphine, thioester, thioether, acid halide, anhydride, oxime, hydrozine, carbamate, phosphonic acid, phosphonate, or any other viable functional group
- aryl phenyl; naphthyl; phenylmethyl; phenylethyl; 3,4,5-trihydroxyphenyl; 3,4,5- trimethoxyphenyl; 3,4,5-triethoxy-phenyl; 4-chlorophenyl; 4-methylphenyl; 3,5-di- tertiarybutyl- 4-hydroxyphenyl; 4-fluorophenyl; 4-chloro-l -naphthyl; 2-methyl-l- naphthylmethyl; 2-naphthylmethyl; 4-chlorophenylmethyl; 4-t-butylphenyl; 4-t- butylphenylmethyl and the like.
- alkylamino or arylamino refers to an amino group that has one or two alkyl or aryl substituents, respectively.
- halogen includes fluorine, chlorine, bromine and iodine.
- enantiomerically enriched is used throughout the specification to describe a nucleoside which includes at least about 95%, preferably at least 96%, more preferably at least 97%>, even more preferably, at least 98%>, and even more preferably at least about 99%> or more of a single enantiomer of that nucleoside.
- a nucleoside of a particular configuration D or L
- host refers to a unicellular or multicellular organism in which the virus can replicate, including cell lines and animals, and preferably a human.
- the host can be carrying a part of the viral genome, whose replication or function can be altered by the compounds of the present invention.
- the term host specifically refers to infected cells, cells transfected with all or part of the viral genome and animals, in particular, primates (including chimpanzees) and humans.
- the term "host” refers to unicellular or multicellular organism in which abnormal cellular proliferation can be mimicked.
- the term host specifically refers to cells that abnormally proliferate, either from natural or unnatural causes (for example, from genetic mutation or genetic engineering, respectively), and animals, in particular, primates (including chimpanzees) and humans. In most animal applications ofthe present invention, the host is a human patient.
- Veterinary applications in certain indications, however, are clearly anticipated by the present invention (such as bovine viral diarrhea virus in cattle, hog cholera virus in pigs, and border disease virus in sheep).
- pharmaceutically acceptable salt or prodrug is used throughout the specification to describe any pharmaceutically acceptable form (such as an ester, phosphate ester, salt of an ester or a related group) of a compound which, upon administration to a patient, provides the active compound.
- Pharmaceutically acceptable salts include those derived from pharmaceutically acceptable inorganic or organic bases and acids. Suitable salts include those derived from alkali metals such as potassium and sodium, alkaline earth metals such as calcium and magnesium, among numerous other acids well known in the pharmaceutical art.
- Pharmaceutically acceptable prodrugs refer to a compound that is metabolized, for example hydrolyzed or oxidized, in the host to form the compound of the present invention.
- prodrugs include compounds that have biologically labile protecting groups on a functional moiety of the active compound.
- Prodrugs include compounds that can be oxidized, reduced, aminated, deaminated, hydroxylated, dehydroxylated, hydrolyzed, dehydrolyzed, alkylated, dealkylated, acylated, deacylated, phosphorylated, dephosphorylated to produce the active compound.
- compositions include those derived from pharmaceutically acceptable inorganic or organic bases and acids.
- Suitable salts include those derived from alkali metals such as potassium and sodium, alkaline earth metals such as calcium and magnesium, among numerous other acids well known in the pharmaceutical art.
- examples of pharmaceutically acceptable salts are organic acid addition salts formed with acids, which form a physiological acceptable anion, for example, tosylate, methanesulfonate, acetate, citrate, malonate, tartarate, succinate, benzoate, ascorbate, ⁇ -ketoglutarate, and ⁇ -glycerophosphate.
- Suitable inorganic salts may also be formed, including, sulfate, nitrate, bicarbonate, and carbonate salts.
- salts may be obtained using standard procedures well known in the art, for example by reacting a sufficiently basic compound such as an amine with a suitable acid affording a physiologically acceptable anion.
- a sufficiently basic compound such as an amine
- a suitable acid affording a physiologically acceptable anion.
- Alkali metal (for example, sodium, potassium or lithium) or alkaline earth metal (for example calcium) salts of carboxylic acids can also be made.
- nucleosides described herein can be administered as a nucleotide prodrug to increase the activity, bioavailability, stability or otherwise alter the properties of the nucleoside.
- a number of nucleotide prodrug ligands are known.
- alkylation, acylation or other lipophilic modification of the mono, di or triphosphate of the nucleoside will increase the stability of the nucleotide.
- substituent groups that can replace one or more hydrogens on the phosphate moiety are alkyl, aryl, steroids, carbohydrates, including sugars, 1,2-diacylgIycerol and alcohols. Many are described in R. Jones and N. Bischofberger, Antiviral Research, 27 (1995) 1-17. Any of these can be used in combination with the disclosed nucleosides to achieve a desired effect.
- the active nucleoside can also be provided as a 5'-phosphoether lipid or a 5 '-ether lipid, as disclosed in the following references, which are incorporated by reference herein: Kucera, L.S., N. Iyer, E. Leake, A. Raben, Modest E.K., D.L.W., and C. Piantadosi. 1990. "Novel membrane-interactive ether lipid analogs that inhibit infectious HIV-1 production and induce defective virus formation.” AIDS Res. Hum. Retro Viruses. 6:491-501; Piantadosi, C, J. Marasco C.J., S.L. Morris-Natschke, K.L. Meyer, F. Gumus, J.R. Surles, K.S.
- Nonlimiting examples of U.S. patents that disclose suitable lipophilic substituents that can be covalently incorporated into the nucleoside, preferably at the 5' -OH position of the nucleoside or lipophilic preparations include U.S. Patent Nos. 5,149,794 (Sep. 22, 1992, Yatvin et al); 5,194,654 (Mar. 16, 1993, Hosteller et al, 5,223,263 (June 29, 1993, Hosteller et al); 5,256,641 (Oct. 26, 1993, Yatvin et al); 5,411,947 (May 2, 1995, Hosteller et al); 5,463,092 (Oct.
- lipophilic substituents that can be attached to the nucleosides of the present invention, or lipophilic preparations, include WO 89/02733, W0 90/00555, W0 91/16920, W0 91/18914, W0 93/00910, W0 94/26273, W0 96/15132, EP 0 350 287, EP 93917054.4, and W0 91/19721.
- compositions based upon a ⁇ -D or ⁇ -L compound of formula (I) - (XXIII) or its pharmaceutically acceptable salt or prodrug can be prepared in a therapeutically effective amount for treating a Flaviviridae, Orthomyxoviridae or Paramyxoviridae viral infection or abnormal cellular proliferation, optionally in combination with a pharmaceutically acceptable additive, carrier or excipient.
- the therapeutically effective amount may vary with the infection or condition to be treated, its severity, the treatment regimen to be employed, the pharmacokinetics ofthe agent used, as well as the patient treated.
- the compound according to the present invention is formulated preferably in admixture with a pharmaceutically acceptable carrier.
- a pharmaceutically acceptable carrier In general, it is preferable to administer the pharmaceutical composition in orally administrable form, but formulations may be administered via parenteral, intravenous, intramuscular, transdermal, buccal, subcutaneous, suppository or other route. Intravenous and intramuscular formulations are preferably administered in sterile saline.
- One of ordinary skill in the art may modify the formulation within the teachings of the specification to provide numerous formulations for a particular route of administration without rendering the compositions of the present invention unstable or compromising its therapeutic activity.
- a modification of a desired compound to render it more soluble in water or other vehicle for example, may be easily accomplished by routine modification (salt formulation, esterification, etc.).
- the prodrug form of the compound especially including acylated (acetylated or other) and ether derivatives, phosphate esters and various salt forms ofthe present compounds, is preferred.
- acylated (acetylated or other) and ether derivatives, phosphate esters and various salt forms ofthe present compounds is preferred.
- One of ordinary skill in the art will recognize how to readily modify the present compound to a prodrug form to facilitate delivery of active compound to a targeted site within the host organism or patient.
- the artisan also will take advantage of favorable pharmacokinetic parameters of the prodrug form, where applicable, in delivering the desired compound to a targeted site within the host organism or patient to maximize the intended effect ofthe compound in the treatment of Flaviviridae (including HCV), Orthomyxoviridae (including Influenza A and B), Paramyxoviridae (including RSV) infections or conditions related to abnormal cellular proliferation.
- Flaviviridae including HCV
- Orthomyxoviridae including Influenza A and B
- Paramyxoviridae including RSV infections or conditions related to abnormal cellular proliferation.
- the amount of compound included within therapeutically active formulations, according to the present invention is an effective amount for treating the infection or condition, in preferred embodiments, a Flaviviridae (including HCV), Orthomyxoviridae (including Influenza A and B), Paramyxoviridae (including RSV) infection or a condition related to abnormal cellular proliferation.
- a therapeutically effective amount of the present compound in pharmaceutical dosage form usually ranges from about 0.1 mg/kg to about 100 mg/kg or more, depending upon the compound used, the condition or infection treated and the route of administration.
- a prophylactically or preventively effective amount of the compositions, according to the present invention falls within the same concentration range as set forth above for therapeutically effective amount and is usually the same as a therapeutically effective amount.
- Administration of the active compound may range from continuous (intravenous drip) to several oral administrations per day (for example, Q.I.D., B.I.D., etc.) and may include oral, topical, parenteral, intramuscular, intravenous, subcutaneous, transdermal (which may include a penetration enhancement agent), buccal and suppository administration, among other routes of administration.
- Enteric-coated oral tablets may also be used to enhance bioavailability and stability of the compounds from an oral route of administration.
- the most effective dosage form will depend upon the pharmacokinetics of the particular agent chosen, as well as the severity of disease in the patient. Oral dosage forms are particularly preferred, because of ease of administration and prospective favorable patient compliance.
- a therapeutically effective amount of one or more of the compounds according to the present invention is preferably mixed with a pharmaceutically acceptable carrier according to conventional pharmaceutical compounding techniques to produce a dose.
- a carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g., oral or parenteral.
- any of the usual pharmaceutical media may be used.
- suitable carriers and additives including water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like may be used.
- suitable carriers and additives including starches, sugar carriers, such as dextrose, mannitol, lactose and related carriers, diluents, granulating agents, lubricants, binders, disintegrating agents and the like may be used. If desired, the tablets or capsules may be enteric-coated for sustained release by standard techniques. The use of these dosage forms may significantly impact the bioavailability of the compounds in the patient.
- the carrier will usually comprise sterile water or aqueous sodium chloride solution, though other ingredients, including those that aid dispersion, also may be included. Where sterile water is to be used and maintained as sterile, the compositions and carriers must also be sterilized. Injectable suspensions may also be prepared, in which case appropriate liquid carriers, suspending agents and the like may be employed.
- Liposomal suspensions may also be prepared by conventional methods to produce pharmaceutically acceptable carriers. This may be appropriate for the delivery of free nucleosides, acyl nucleosides or phosphate ester prodrug forms of the nucleoside compounds according to the present invention.
- the compounds and compositions are used to treat, prevent or delay the onset of Flaviviridae (including HCV), Orthomyxoviridae (including Influenza A and B), Paramyxoviridae (including RSV) infections or conditions related to abnormal cellular proliferation.
- the compositions will be administered in oral dosage form in amounts ranging from about 250 micrograms up to about 1 gram or more at least once a day, preferably, or up to four times a day.
- the present compounds are preferably administered orally, but may be administered parenterally, topically or in suppository form.
- the compounds according to the present invention may be advantageously employed prophylactically to prevent Flaviviridae (including HCV), Orthomyxoviridae (including Influenza A and ), Paramyxoviridae (including RSV) infections or conditions related to abnormal cellular proliferation or to prevent the occurrence of clinical symptoms associated with the viral infection or condition.
- the present invention also encompasses methods for the prophylactic treatment of viral infection, and in particular Flaviviridae (including HCV), Orthomyxoviridae (including Influenza A and B), Paramyxoviridae (including RSV) infections or of a condition related to abnormal cellular proliferation.
- the present compositions are used to prevent or delay the onset of a Flaviviridae (including HCV), Orthomyxoviridae (including Influenza A and B ⁇ Paramyxoviridae (including RSV) infection or a condition related to abnormal cellular proliferation.
- This prophylactic method comprises administration to a patient in need of such treatment, or who is at risk for the development of the virus or condition, an amount of a compound according to the present invention effective for alleviating, preventing or delaying the onset of the viral infection or condition.
- the antiviral or antiproliferative compound utilized should be low in toxicity and preferably non-toxic to the patient.
- the compound that is used should be maximally effective against the virus or condition and should exhibit a minimum of toxicity to the patient.
- Flaviviridae including HCV
- Orthomyxoviridae including Influenza A and B
- Paramyxoviridae including RSV
- compounds according to the present invention may be administered within the same dosage range for therapeutic treatment (i.e., about 250 micrograms up to 1 gram or more from one to four times per day for an oral dosage form) as a prophylactic agent to prevent the proliferation of a Flaviviridae (including HCV), Orthomyxoviridae (including Influenza A and B ⁇ Paramyxoviridae (including RSV) infections or conditions related to abnormal cellular proliferation, or alternatively, to prolong the onset of a Flaviviridae (including HCV), Orthomyxoviridae (including Influenza A and B), Paramyxovi
- compounds according to the present invention can be administered in combination or alternation with one or more antiviral, anti-HBV, anti-HCV or anti- herpetic agent or interferon, anti-cancer or antibacterial agents, including other compounds of the present invention.
- Certain compounds according to the present invention may be effective for enhancing the biological activity of certain agents according to the present invention by reducing the metabolism, catabolism or inactivation of other compounds and as such, are co-administered for this intended effect.
- Drug resistance most typically occurs by mutation of a gene that encodes for an enzyme used in the viral replication cycle, and most typically in the case of HCV, the RNA-dependent-RNA polymerase. It has been demonstrated that the efficacy of a drug against viral infection can be prolonged, augmented, or restored by administering the compound in combination or alternation with a second, and perhaps third, antiviral compound that induces a different mutation from that caused by the principle drug. Alternatively, the pharmacokineti.es, biodistribution or other parameter of the drug can be altered by such combination or alternation therapy. In general, combination therapy is typically preferred over alternation therapy because it induces multiple simultaneous stresses on the virus.
- agents that have been identified as active against the hepatitis C virus, and thus can be used in combination or alternation with one or more nucleosides of general formula (I) - (XXIII) include:
- Non-substrate-based inhibitors such as 2,4,6-trihydroxy-3-nitro-benzamide derivatives (Sudo K. et al, Biochemical and Biophysical Research Communications, 1997, 238, 643 and Sudo K et al Antiviral Chemistry and Chemotherapy 1998, 9, 186), including RD3-4082 and RD3-4078, the former substituted on the amide with a 14 carbon chain and the latter processing a ⁇ r ⁇ -phenoxyphenyl group;
- HCV helicase inhibitors (Diana G. D. et al, U.S. Patent No. 5,633,358 and Diana G. D. et al. PCT WO 97/36554);
- HCV polymerase inhibitors such as nucleotide analogues, gliotoxin (Ferrari R. et al. Journal of Virology 1999, 73, 1649), and the natural product cerulenin (Lohmann V. et al. Virology 1998, 249, 108);
- S-ODN Antisense phosphorothioate oligodeoxynucleotides (S-ODN) complementary to at least a portion of a sequence ofthe HCV (Anderson et al. U.S. Patent No. 6,174,868), and in particular the sequence stretches in the 5' non-coding region (NCR) (Alt M. et al. Hepatology 1995, 22, 707), or nucleotides 326-348 comprising the 3' end of the NCR and nucleotides 371-388 located in the core coding region of the HCV RNA (Alt M. et al Archives of Virology 1997, 142, 589 and Galderisi U. et al, Journal of Cellular Physiology 1999, 57:2151);
- Amantadine such as rimantadine (Smith, Abstract from Annual Meeting of the American Gastoenterological Association and AASLD, 1996);
- Quinolones such as ofloxacin, ciprofloxacin and levofloxacin (AASLD Abstracts, Hepatology, Oct. 1994, Program Issue, 20 (4), pt.2, abstract no. 293);
- Nucleoside analogs (Ismaili et al WO 01/60315; Siorer WO 01/32153), including 2'- deoxy-L-nucleosides (Watanabe et al. WO 01/34618), and l-( ⁇ -L-ribofuranosyl)- l,2,4-triazole-3-carboxamide (levovirinTM) (Tam WO 01/46212); and
- agents that have been identified as active against the influenza virus include: (a) actinomycin D (Barry, R. D. et al. "Participation of deoxyribonucleic acid in the multiplication of influenza virus” Nature, 1962, 194, 1139-1140);
- amantadine (Van Voris, L. P. et al. "Antivirals for the chemoprophylaxis and treatment of influenza" Semin Respir Infect, 1992, 7, 61-70);
- interferon (e) interferon (Came, P. E. et al. "Antiviral activity of an interferon-inducing synthetic polymer” Proc Soc Exp Biol Med, 1969, 131, 443-446; Gerone, P. J. et al. "Inhibition of respiratory virus infections of mice with aeresols of synthetic double- stranded ribonucleic acid” Infect Immun, 1971, 3, 323-327; Takano, K. et al. "Passive interferon protection in mouse influenza” J Infect Dis, 1991, 164, 969-972);
- RSV drug-resistant variants of RSV can emerge after prolonged treatment with an antiviral agent. Drug resistance most typically occurs by mutation of a gene that encodes for an enzyme used in the viral replication cycle. It has been demonstrated that the efficacy of a drug against RSV infection can be prolonged, augmented, or restored by administering the compound in combination or alternation with a second, and perhaps third, antiviral compound that induces a different mutation from that caused by the principle drug. Alternatively, the pharmacokinetics, biodistribution or other parameter of the drug can be altered by such combination or alternation therapy. In general, combination therapy is typically preferred over alternation therapy because it induces multiple simultaneous stresses on the virus.
- agents that have been identified as active against RSV and thus can be used in combination or alternation with one or more nucleosides of general formula (I) - (XXIII) include:
- agents that have been identified as active against abnormal cellular proliferation include:
- Nitrogen Mustards Mechlorethamine (Hodgkin's disease, non-Hodgkin's lymphomas), Cyclophosphamide, Ifosfamide (acute and chronic lymphocytic leukemias, Hodgkin's disease, non-Hodgkin's lymphomas, multiple myeloma, neuroblastoma, breast, ovary, lung, Wilms' tumor, cervix, testis, soft-tissue sarcomas), Melphalan (L-sarcolysin) (multiple myeloma, breast, ovary), Chlorambucil (chronic lymphoctic leukemia, primary macroglobulinemia, Hodgkin's disease, non-Hodgkin's lymphomas).
- Ethylenimines and Methylmelamines Hexamethylmelamine (ovary), Thiotepa (bladder, breast, ovary).
- Alkyl Sulfonates Busulfan (chronic granuloytic leukemia).
- BCNU Carmustine
- CCNU Hodgkin's disease, non-Hodgkin's lymphomas, primary brain tumors, multiple myeloma, malignant melanoma
- CCNU Lomustine
- CCNU Hodgkin's disease, non-Hodgkin's lymphomas, primary brain tumors, small-cell lung
- Semustine methyl-CCNU
- STR Streptozocin
- Triazenes dacarbazine (DTIC; dimethyltriazenoimidazole-carboxamide) (malignant melanoma, Hodgkin's disease, soft-tissue sarcomas).
- DTIC dacarbazine
- dimethyltriazenoimidazole-carboxamide malignant melanoma, Hodgkin's disease, soft-tissue sarcomas.
- Methotrexate (amethopterin) (acute lymphocytic leukemia, choriocarcinoma, mycosis fungoides, breast, head and neck, lung, osteogenic sarcoma).
- Fluorouracil (5-fluorouracil; 5-FU) Floxuridine (fluorodeoxyuridine; FUdR) (breast, colon, stomach, pancreas, ovary, head and neck, urinary bladder, premalignant skin lesions) (topical), Cytarabine (cytosine arabinoside) (acute granulocytic and acute lymphocytic leukemias).
- Mercaptopurine (6-mercaptopurine; 6-MP) (acute lymphocytic, acute granulocytic and chronic granulocytic leukemia), Thioguanine (6-thioguanine: TG) (acute granulocytic, acute lymphocytic and chronic granulocytic leukemia), Pentostatin (2'-deoxycyoformycin) (hairy cell leukemia, mycosis fungoides, chronic lymphocytic leukemia).
- 6-MP acute lymphocytic, acute granulocytic and chronic granulocytic leukemia
- Thioguanine (6-thioguanine: TG) (acute granulocytic, acute lymphocytic and chronic granulocytic leukemia)
- Pentostatin (2'-deoxycyoformycin) (hairy cell leukemia, mycosis fungoides, chronic lymphocytic leukemia).
- Vinca Alkaloids Vinblastine (VLB) (Hodgkin's disease, non-Hodgkin's lymphomas, breast, testis), Vincristine (acute lymphocytic leukemia, neuroblastoma, Wilms' tumor, rhabdomyosarcoma, Hodgkin's disease, non-Hodgkin's lymphomas, small- cell lung).
- VLB Vinblastine
- Vincristine acute lymphocytic leukemia, neuroblastoma, Wilms' tumor, rhabdomyosarcoma
- Hodgkin's disease non-Hodgkin's lymphomas, small- cell lung.
- Epipodophylotoxins Etoposide (testis, small-cell lung and other lung, breast, Hodgkin's disease, non-Hodgkin's lymphomas, acute granulocytic leukemia, Kaposi's sarcoma), Teniposide (testis, small-cell lung and other lung, breast, Hodgkin's disease, non-Hodgkin's lymphomas, acute granulocytic leukemia, Kaposi's sarcoma).
- Dactinomycin actinonmycin D
- choriocarcinoma Wilms' tumor rhabdomyosarcoma, testis, Kaposi's sarcoma
- Daunorubicin daunomycin; rubidomycin
- Doxorubicin soft tissue, osteogenic, and other sarcomas
- Hodgkin's disease non-Hodgkin's lymphomas, acute leukemias, breast, genitourinary thyroid, lung, stomach, neuroblastoma
- Bleomycin testis, head and neck, skin and esophagus lung, and genitourinary tract
- Hodgkin's disease, non-Hodgkin's lymphomas Plicamycin (mithramycin) (testis, malignant hypercalcema), Mitomycin (mitomycin C) (stomach, cervix, colon,
- Enzymes L-Asparaginase (acute lymphocytic leukemia).
- Interferon- alfa hairy cell leukemia, Kaposi's sarcoma, melanoma, carcinoid, renal cell, ovary, bladder, non Hodgkin's lymphomas, mycosis fungoides, multiple myeloma, chronic granulocytic leukemia).
- Cisplatin cis-DDP
- Carboplatin testis, ovary, bladder, head and neck, lung, thyroid, cervix, endometrium, neuroblastoma, osteogenic sarcoma).
- Anthracenedione Mixtozantrone (acute granulocytic leukemia, breast).
- Substituted Urea Hydroxyurea (chronic granulocytic leukemia, polycythemia vera, essential thrombocytosis, malignant melanoma).
- Methylhydrazine Derivative Procarbazine (N-methylhydrazine, MIH) (Hodgkin's disease).
- Mitotane o,p'-DDD (adrenal cortex)
- Adrenorticosteriods Prednisone (acute and chronic lymphocytic leukemias, non- Hodgkin's lymphomas, Hodgkin's disease, breast).
- Progestins Hydroxprogesterone caproate, Medroxyprogesterone acetate, Megestrol acetate (endometrium, breast).
- Estrogens Diethylstibestrol Ethinyl estradiol (breast, prostate)
- Antiestrogen Tamoxifen (breast).
- Testosterone propionate Fluxomyesterone (breast).
- Antiandrogen Flutamide (prostate).
- Compounds of formula (I) - (XXIII) can be synthesized by any means known in the art.
- the compounds can be made via three distinct routes: (a) from a preformed nucleoside, (b) condensation of a modified sugar or unmodified ribose with purine or pyrimidine, and (c) combination of the two routes. Since the 3-deoxy-D- erythropentofuranose structure is found in the nucleoside antibiotic, cordycepin, a number of total syntheses of this antibiotic have been reported during 1960s (see: Lee, W. W. et al. J. Am. Chem. Soc, 1961, 83, 1906; Walton, E. et al. J. Am. Chem.
- N 4 -protected-cytidine nucleosides can be derivatized to form pyrimidine nucleosides (I-a) as shown in Scheme 1.
- N -protected-D-cytidine nucleoside 1 can be treated with an acid halide, such as acetyl bromide, to give the corresponding 3'-halo-xylo-nucleoside 2.
- an acid halide such as acetyl bromide
- Deacetylation of 2 to 3, followed reductive dehalogenation affords the desired 3'-deoxycytidine derivatives 4.
- Treatment of 2 with an acid, preferably boiling aqueous acetic acid gives the corresponding protected uracil nucleoside 5, which can be readily converted into free 3'- bromo-xylo nucleoside 6a, from which 3'-deoxyuridine derivatives 6b can be obtained by reductive debromination.
- the L-enantiomer (Ill-a) of 4 and 6 can be synthesized.
- Treatment of 8 with diluted potassium or sodium hydroxide gives the corresponding xylo derivative 10 via anhydronucleoside 9, which, after de-O-tritylation, affords 12.
- Mesylation of 10, followed by de-O-tritylation yields the 3'-O-mesyl xylo-nucleoside.
- the corresponding 3'-deoxy-3'-halogeno derivative 11 is formed via 9, which, after de-O-tritylation, followed by hydrogenolysis, is converted into the desired 3'- deoxyuridine derivative 6b.
- the L- nucleoside (IH-a) counte ⁇ arts of 4 and 6 are synthesized.
- type I-b compound, purine nucleoside is the synthesis of 3'-deoxypurine nucleosides (Scheme 3).
- Hydrogenolysis, followed by chromatographic separation affords the corresponding 3'-deoxynucleoside 17 along with the 2'-deoxynucleoside 16. Saponification of 17 gives the desired 3'-deoxynucleoside 20.
- the L-nucleoside counte ⁇ art of 20, which belongs to III-b can be synthesized.
- the starting material is a 5- nitropyrimidine or pyridine nucleoside (Scheme 4).
- 5-nitrouridine 21, vide supra
- azide ion in a solvent such as alcohol or dimethylformamide at a temperature range of from 20 °C to 100 °C, preferably from 25 °C to 80 °C.
- Nucleophilic attack of azide ion at C-6 of 21 results in the formation of ⁇ ct-nitro salt 22 which cyclizes to 23.
- Neutralization of 23 furnishes the bicyclic nucleoside 24.
- l,2-O-Isopropylidene-5-O-methoxycarbonyl- ⁇ -D-xylo-furanose (25) is converted into the corresponding 3 -thiocarbonyl derivative26, followed by free radical deoxygenation using trialkyltin hydride in the presence of a radical initiator, such as 2,2'- azobisisobutyronitrile.
- the deoxygenated product 27 is acylated with a mixture of acetic acid, acetic anhydride and sulfuric acid to give 28, which then is condensed with a silylated base using Vorbruggen's procedure (.see: Niedballa, U. et al. J. Org.
- the 5-OH group can be alternatively protected with other acyl groups, such as benzoyls, yp-nitrobenzoyls, -chlorobenzoyls or p- methoxybenzoyls as well as other silyl groups, such as t-butyldimethylsilyl or t- butyldiphenyl groups.
- acyl groups such as benzoyls, yp-nitrobenzoyls, -chlorobenzoyls or p- methoxybenzoyls
- silyl groups such as t-butyldimethylsilyl or t- butyldiphenyl groups.
- L-xylose can be converted into the L-sugar counte ⁇ art of 25, which can be further derivatized to attain the L-nucleoside of 30.
- l,2-O-isopropylidene-5-O-(t- butyldiphenylsilyl)- ⁇ -D-xylofuranose (31) can be sulfonylated with mesyl chloride, tosyl chloride or tresyl chloride in pyridine to obtain32.
- the methyl xyloside 33 can be treated with a base, such as sodium methoxide in methanol, to afford the ribo-epoxide 34. Opening of the epoxide 34 with lithium aluminum hydride stereoselectively produces 3-deoxy sugar 36.
- acetylated sugars 38 and 40 can be condensed with pertrimethylsilylated pyrimidine or purine bases using Vorbrueggen's procedure to give the 3 '-modified nucleoside.
- the t- butyldiphenylsilyl protecting group can be replaced by t-butyldimethylsilyl group.
- a nucleophile such as hydroxylamine
- the 5- chloro, 5-bromo and 5-iodouridine derivatives (50-52) are obtained using the appropriate N-halogenosuccinimde.
- Compound 60 alternatively can be treated with dihydropyran and a catalytic amount of acid, such as hydrochloric, sulfuric or ⁇ -toluenesulfonic acid, to yield the 2',5'-di-O-protected nucleoside 64.
- acid such as hydrochloric, sulfuric or ⁇ -toluenesulfonic acid
- a catalytic amount of acid such as hydrochloric, sulfuric or ⁇ -toluenesulfonic acid
- DAST diethylaminosulftir trifluoride
- aqueous buffer 6 or 4 can be treated with mercuric acetate, followed by sodium chloride, to give the corresponding 5-chloromercuri derivative 87 or 91, respectively (Scheme 14), in quantitative yield.
- Reaction of 87 or 91 with iodine in ethanol gives the 5-iodo derivative 52 or 56, respectively.
- Compound 52 can be converted to 5-ethynyl derivatives 88 by reaction with 1-alkynes and bis(triphenylphosphine)palladium chloride (Ph 3 P) 2 PdCl 2 in the presence of cuprous iodide and triethylamine.
- Methyl acrylate reacts with 87 or 91 in the presence of Li 2 PdCl 2 to give 5-(E)-(2-methoxy-carbonyl)vinyl-3'- deoxyuridine (83) or -cytidine (92), respectively.
- Compound 28 or 38 is converted into halogenase 122 (Scheme 18) by treatment with hydrogen chloride or hydrogen bromide in acetic acid or hydrogen bromide in dichloromethane and condensed with 6-chloropurine by the sodio procedure in acetonitrile affords 3'-deoxynucleoside 123.
- Aqueous sodium or potassium hydroxide treatment of 123 gives 3'-deoxyinosine (124).
- Treatment of 123 with sodium methoxide in methanol affords 6-O-methyl-3'-deoxyinosine (125).
- Mild saponification, followed by catalytic hydrogenolysis of 123 results in the production of 3'-deoxynebularine (126).
- Thiourea reacts with 123 to give 6-thiopurine nucleoside 127, which is S-alkylated to 128.
- Compounds 123, 127 and 128 readily react with various amines, hydroxylamine, hydrazine and aminoalcohols to give 3'-deoxyadenosine analogues 129-133.
- Treatment of 123 with sodium azide gives 6-azidopurine nucleoside 134.
- These compounds can also be synthesized by nitrous acid treatment of 6- hydrazidopurine nucleoside 130. Reduction of 129, 130 or 134 gives 3'-deoxyadenosine (i.e., cordycepin). Compound 125 or cordycepin are expected to be converted in vivo into 124 by action of adenosine deaminase. 6-Unsubstituted purine nucleoside 126 may be oxidized in vivo to 124.
- the 2-amino group of 135-147 can be modified to obtain 155 (Scheme 21) by acylation with various alkanoyl or aroyl halides. Then, 155 can further be derivatized into the corresponding 2-alkylamino or 2-arylamino derivative 156 by reduction with a borane- a ine complex (Sergueeva, Z. A. et al. Nucleosides Nucleotides Nucleic Acids, 2000, 19, 275).
- the 2-amino group of compound 135 can be substituted by undergoing a Schiemann reaction, diazotizing in the presence of fluoroborate, followed by thermal decomposition, to give 2-fluoro-6-chloropurine nucleoside 157.
- the 6-chloro substituent of these nucleosides can be displaced with various nucleophilic reagents as described above. It should be noted that the presence of 2-fluoro substituent protects the 6-amino group from adenosine deaminase attack.
- the C-8 bromine substituent in 159-161 can be replaced with sulfur by the action of thiourea to obtain 162-164, which can be alkylated or aralkylated with alkyl or aralkyl halide in a polar solvent, such as water, alcohol or dimethylformamide, in the presence of base, such as sodium or potassium carbonate, to give 165-167.
- a polar solvent such as water, alcohol or dimethylformamide
- base such as sodium or potassium carbonate
- 8-amino derivatives can be obtained directly from 159-161 by treatment with amines.
- 159 can be converted into the 8- oxo derivative 174 by treatment with sodium acetate in acetic anhydride, followed by hydrolysis.
- O-Alkylation of 174 with triethyloxonium fluoroborate gives 8- ethoxycordycepin 175.
- Mesylation of 184 gives in high yield of the olifm 186 via 185.
- Compound 185 can be isolated in poor yield after short reaction time.
- De-O- silyation of 186 with fluoride, such as tetrabutyl ammonium fluoride affords the desired olefin 187, type Il-a nucleoside, in high yield.
- the type Il-a olefmic sugar nucleoside also can be prepared.
- Sulfonylation of 188 preferably with mesyl chloride in pyridine at temperature range from -10 °C to 80 °C, preferably at room temperature, gives the di-O-mesylate 189, which, upon treatment with aqueous base such as sodium hydroxide solution gives 3',5'-anhydrosugar nucleoside 190.
- nucleoside can be readily converted into the desired 187 in high yield by treatment with strong, anhydrous base, such as with potassium tert-butoxide in dimethylsulfoxide at temperature range of from -10 °C to 80 °C, preferably at room temperature for 10 minutes to overnight, preferably 1.5 to 3 hours.
- strong, anhydrous base such as with potassium tert-butoxide in dimethylsulfoxide at temperature range of from -10 °C to 80 °C, preferably at room temperature for 10 minutes to overnight, preferably 1.5 to 3 hours.
- Sulfonylation of 192 preferably with mesyl chloride in pyridine, gives the mesylate 193, which, upon treatment with non- nucleophilic base, such as DBU or DBN in anhydrous inert solvent, such as methylene chloride, affords 2,3'-anhydro nucleoside 194.
- This compound is readily converted into 2'-fluoro-olefinic sugar nucleoside 195 upon treatment with potassium t-butoxide in dimethylsulfoxide.
- De-protection of 195 gives the desired 2'-fluorinated Il-a type nucleoside 196. 5'-O-Silyl protection gives better overall yield than trityl protection.
- R Tr, SiMe 2 -t-B ⁇ or SiPh 2 -t-Bu
- Nucleosides of type Il-b can be prepared readily from 197 (Scheme 27). Selective protection of 197 at the 5 '-position, e.g., with t-butyldimethylsilyl or t-butyldiphenylsilyl group affords 198. Sulfonylation with tosyl halide or mesyl halide in base such as in pyridine affords the protected olefinic nucleoside 199. De-O-silylation of 199 with fluoride, such as tetrabutyl ammonium fluoride affords the desired olefin 200, type Il-b nucleoside, in high yield.
- fluoride such as tetrabutyl ammonium fluoride
- adenine nucleosides i.e., aristeromycin and neplanocins, and they are either extremely expensive or commercially not available. Thus, these types of nucleosides are chemically synthesized from scratch.
- the c ⁇ r ⁇ -sugar derivative is prepared first and then the heterocyclic aglycon is constructed on the sugar to prepare c ⁇ r& ⁇ -sugar nucleosides or in the case of purine nucleoside, the base is directly condensed with the c ⁇ r ⁇ -sugar.
- Scheme 30 illustrates the synthesis of 5-fluoro-c ⁇ rb ⁇ -cytidine (227, Type V-a).
- the c ⁇ r ⁇ -sugar intermediate 219 can be synthesized by any means known in the art. It is disclosed by Ali et al. (Tetrahedron Letters, 1990, 31, 1509) that D-ribonolactone 217 is converted into the pentanone intermediate 218.
- the ketone 218 can then be reduced by any known reducing agent, preferably sodium borohydride in methanol at 0 °C for 1 hour to afford alcohol 219.
- Protected 5-fluoro-c ⁇ 3r£> ⁇ -uridine (225) can be obtained by fluorination of 224 with any fluorinating agent.
- the fluorinating agent is fluorine in acetic acid.
- base preferably triethylamine.
- Conversion of uracil nucleoside 225 into protected c ⁇ r ⁇ -5-fluorocytidine (226) can be achieved in a similar manner as described with Scheme 7.
- the protecting groups of 226 are removed with acid, preferably with trifluoroacetic acid/water (2:1 v/v) at 50 °C for 3 hours, to give 227.
- the aminoalcohol 232 is converted into 2',3'-O-cyclohexylidene-c ⁇ r6 ⁇ -uridine by reaction with ⁇ -methoxyacryloylisocyanate, followed by ammonia treatment.
- Acid treatment preferably with trifluoroacetic acid in methanol, gives carba-u ⁇ din ⁇ (233).
- c ⁇ 3r ⁇ > ⁇ -5-Fluorocytidine (227) can be obtained readily from 233 by the well-known means in the art.
- Nucleoside of type VI is prepared from nucleoside of type V.
- An example is shown in Scheme 32.
- Aristeromycin (234) or any c ⁇ r ⁇ -ribonucleoside is converted into the corresponding N-[(dimethylamino)methylene]-5 , -O-trityl derivative 235 by treatment with dimethylformamide dimethylacetal in DMF, followed by tritylation.
- silyl protection with t-butyldimethylsilyl or t-butyldiphenylsilyl protection can also be used.
- mesylation instead of mesylation, other sulfonylation using an agent, such as tosyl chloride, triflyl chloride or triflyl anhydride can be used.
- nucleosides of type Vl-b can be synthesized starting from 2-cyclopenten-l- one (250, Scheme 34).
- Michael addition of t-butoxymethyllithiumcuprate [(t- BuOCH 2 ) 2 CuLi] to 250 yields the adduct 251.
- Phenylselenation of 251 according to Wilson et al. (Synthesis, 1995, 1465) mainly occurs trans to t-butoxymethyl group to give 252.
- DIBAH reduction reduces the carbonyl group to hydroxyl group in a stereoselective manner to give 253.
- acetylation of 253, followed by condensation with silylated pyrimidine, such as tris(trimethylsilyl)-5-fluorocytosine in the presence of trimethylsilyl trifluoromethylsulfonate gives high yield of the corresponding pyrimidine nucleoside, from which Vl-a type nucleoside can readily prepared by oxidation and acid removal of t- butyl group ofthe product.
- racemic carba analogues of 2 ',3 '-unsaturated nucleosides can be prepared by the procedure of Shi et al. (J. Med. Chem., 1999, 42, 859) who achieved multi-step preparation of racemic c/s-3,4-epoxy-cyclopentanemethanol 257 (Scheme 35) from ethyl cyclopentene-4-carboxylate. Opening of the epoxide with diphenyldiselenide affords 258, which, after acetylation followed by peroxide treatment, gives diacetate 259.
- sodiopyrimidine prepared by reaction of uracil or cytosine derivative with NaH in dimethylsulfoxide, in the presence of Pd(PPh ) 4 in an inert solvent, e.g., tetrahydrofuran, gives 260 in 10-70% yield after deacetylation of the product.
- 263 CF 3
- nucleosides used in the present invention are prepared mainly in the following manner.
- 1-Mentylester of 2,2-dimethoxyacetic acid (267, Scheme 37) is condensed with thioglycolic acid to give a diastereomeric mixture 268, which can readily be separated on a silica gel column.
- Reduction of 268 with NaBH in ethanol, followed by acetylation affords 269, which is condensed with silylated base in the presence of tin tetrachloride.
- Mainly the desired protected ⁇ -nucleoside is obtained and is purified by chromatography.
- 270 is obtained starting from 2,2-dimethoxyethyl ester of N-t-Boc-L-proline.
- This compound is treated with 3 equivalents of thioglycolic acid in methylene chloride in the presence of MgSO 4 and CAS to give 271 as a diastereomeric mixture, which is separated chromatographically.
- Reduction of each diastereomer of 271 with Li(t-BuO) 3 AlH in tetrahydrofuran and subsequent acetylation affords 272, which is condensed with silylated base, followed by deprotection ofthe product to give 270.
- Nucleosides of type XIII used in this invention are prepared by using means known in the art.
- XIH-a type nucleosides are prepared in one or two-step synthesis reported (Nucleic Acid Chem., 1978, 1, 272 and 343) by activating the 5'-OH by sulfonylation followed by base treatment or direct treatment of unprotected nucleosides with Ph3P and diethyl diazocarboxylate.
- nucleosides of type XIV used in the present invention are synthesized by methods somewhat analogous to those utilized for the synthesis of the corresponding 5-fluorodeoxyuridine adducts by Duschinsky et al. (J. Med. Chem., 1967, 10, 47). Some examples are shown in Scheme 38 using 5-fluorouridine (273). Any pyrimidine nucleoside containing a strongly electron-withdrawing substituent at C-5 undergoes similar adduct formation. Treatment of 273 with bromine in methanol gives adduct 274 which can be reduced to 275 by catalytic hydrogenation.
- bromohydrin 277 Treatment in water gives the bromohydrin 277 while action of bromine in acetic acid in the presence of acetic anhydride affords 276.
- the corresponding other adducts can be prepared by using other hypohalites, e.g., hypochlorite gives 278. Each of these adducts are diastereomeric mixture and are used for screening as such.
- Nucleosides used in this invention are prepared by oxidation of 4-thiouridine and 6-thioinosine derivatives according to the well-known means in the art.
- Type XVI compounds are C-nucleosides.
- XVI-a nucleosides are synthesized from ⁇ -uridine by methods known in the art (Watanabe, "The Chemistry of C-Nucleosides", Townsend, L. B., Ed., In “ Chemistry of Nucleosides and Nucleotides”, Plenum, Publ., New York, Vol., 3, 421, 1994), or condensation of an aromatic compound to protected ribonolactone, followed by manupulation of the products (e.g., Rabat et al, J. Med.
- Nucleosides XVI-b and XVI-c are prepared according to a modified procedure developed by Pankiewicz et al, (Carbohydr. Res., 1984, 127, 227; Nucleosides Nucleotides, 1991, 10, 1333).
- the purine-type XVI-d C-nucleosides are synthesized according to the method reported by Chu et al, (J. Heterocycl. Chem., 1980, 17, 1435).
- Nucleosides of type XVII used in this invention are synthesized either by cross-aldol reaction of 4'-formyl nucleosides with formaldehyde or condensation of preformed sugar with a base. Preparation of some of the type XVIII nucleosides have already discussed earlier.
Abstract
Description
Claims
Priority Applications (14)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DK01987756.2T DK1411954T3 (en) | 2000-10-18 | 2001-10-18 | Modified nucleosides to treat viral infections and abnormal cellular proliferation |
EP01987756A EP1411954B1 (en) | 2000-10-18 | 2001-10-18 | Modified nucleosides for treatment of viral infections and abnormal cellular proliferation |
KR1020107014460A KR101201552B1 (en) | 2000-10-18 | 2001-10-18 | Modified nucleosides for treatment of viral infections and abnormal cellular proliferation |
AT01987756T ATE491459T1 (en) | 2000-10-18 | 2001-10-18 | MODIFIED NUCLEOSIDES FOR THE TREATMENT OF VIRUS INFECTIONS AND ABNORMAL CELLULAR PROLIFERATION |
KR10-2003-7005461A KR20040028657A (en) | 2000-10-18 | 2001-10-18 | Modified nucleosides for treatment of viral infections and abnormal cellular proliferation |
CA2426187A CA2426187C (en) | 2000-10-18 | 2001-10-18 | Modified nucleosides for the treatment of viral infections and abnormal cellular proliferation |
DE60143672T DE60143672D1 (en) | 2000-10-18 | 2001-10-18 | MODIFIED NUCLEOSIDES FOR THE TREATMENT OF VIRUS INFECTIONS AND ABNORMAL CELLULAR PROLIFERATION |
AU2002228749A AU2002228749B2 (en) | 2000-10-18 | 2001-10-18 | Modified nucleosides for treatment of viral infections and abnormal cellular proliferation |
BRPI0114837-0A BR0114837A (en) | 2000-10-18 | 2001-10-18 | modified nucleosides for treatment of viral infections and abnormal cell proliferation |
CN01820816.9A CN1646141B (en) | 2000-10-18 | 2001-10-18 | Modified nucleosides for treatment of viral infections and abnormal cellular proliferation |
KR1020117007042A KR101195019B1 (en) | 2000-10-18 | 2001-10-18 | Modified nucleosides for treatment of viral infections and abnormal cellular proliferation |
AU2874902A AU2874902A (en) | 2000-10-18 | 2001-10-18 | Modified nucleosides for treatment of viral infections and abnormal cellular proliferation |
JP2002536301A JP2004533406A (en) | 2000-10-18 | 2001-10-18 | Modified nucleosides for treating viral infections and abnormal cell proliferation |
HK05110563.1A HK1078482A1 (en) | 2000-10-18 | 2005-11-22 | Modified nucleosides for treatment of viral infections and abnormal cellular proliferation |
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US24148800P | 2000-10-18 | 2000-10-18 | |
US60/241,488 | 2000-10-18 | ||
US28215601P | 2001-04-06 | 2001-04-06 | |
US60/282,156 | 2001-04-06 |
Publications (2)
Publication Number | Publication Date |
---|---|
WO2002032920A2 true WO2002032920A2 (en) | 2002-04-25 |
WO2002032920A3 WO2002032920A3 (en) | 2004-02-19 |
Family
ID=26934330
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US2001/046113 WO2002032920A2 (en) | 2000-10-18 | 2001-10-18 | Modified nucleosides for treatment of viral infections and abnormal cellular proliferation |
Country Status (16)
Country | Link |
---|---|
US (3) | US20030087873A1 (en) |
EP (2) | EP2251015B1 (en) |
JP (4) | JP2004533406A (en) |
KR (6) | KR20040028657A (en) |
CN (2) | CN101862345B (en) |
AT (1) | ATE491459T1 (en) |
AU (4) | AU2874902A (en) |
BR (1) | BR0114837A (en) |
CA (1) | CA2426187C (en) |
CY (1) | CY1111332T1 (en) |
DE (1) | DE60143672D1 (en) |
DK (2) | DK1411954T3 (en) |
ES (1) | ES2402597T3 (en) |
HK (2) | HK1078482A1 (en) |
PT (2) | PT2251015E (en) |
WO (1) | WO2002032920A2 (en) |
Cited By (198)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2002094289A1 (en) * | 2001-05-23 | 2002-11-28 | F. Hoffmann-La Roche Ag | Antiviral nucleoside derivatives |
WO2003061576A2 (en) * | 2002-01-17 | 2003-07-31 | Ribapharm Inc. | Deazapurine nucleoside analogs and their use as therapeutic agents |
WO2003068244A1 (en) * | 2002-02-13 | 2003-08-21 | Merck & Co., Inc. | Methods of inhibiting orthopoxvirus replication with nucleoside compounds |
WO2004046331A2 (en) | 2002-11-15 | 2004-06-03 | Idenix (Cayman) Limited | 2’-branched nucleosides and flaviviridae mutation |
WO2004062676A1 (en) * | 2003-01-09 | 2004-07-29 | F. Hoffmann-La Roche Ag | -modified nucleoside derivatives for treating flaviviridae infections |
US6777395B2 (en) | 2001-01-22 | 2004-08-17 | Merck & Co., Inc. | Nucleoside derivatives as inhibitors of RNA-dependent RNA viral polymerase of hepatitis C virus |
US6812219B2 (en) | 2000-05-26 | 2004-11-02 | Idenix Pharmaceuticals, Inc. | Methods and compositions for treating flaviviruses and pestiviruses |
WO2005003147A2 (en) | 2003-05-30 | 2005-01-13 | Pharmasset, Inc. | Modified fluorinated nucleoside analogues |
WO2005009418A3 (en) * | 2003-07-25 | 2005-04-07 | Idenix Cayman Ltd | Purine nucleoside analogues for treating diseases caused by flaviviridae including hepatitis c |
WO2005042557A1 (en) * | 2003-10-30 | 2005-05-12 | Sumitomo Chemical Company, Limited | Method for producing purine compound |
US6914054B2 (en) | 2000-05-23 | 2005-07-05 | Idenix Pharmaceuticals, Inc. | Methods and compositions for treating hepatitis C virus |
EP1569652A2 (en) * | 2001-12-14 | 2005-09-07 | Pharmasset Ltd. | N sp 4 /sp-acylcytosine nucleosides for treatment of viral iinfections |
WO2005097757A2 (en) * | 2004-04-01 | 2005-10-20 | Rexahn Corporation | Nucleoside derivatives and therapeutic use thereof |
WO2005123087A2 (en) | 2004-06-15 | 2005-12-29 | Merck & Co., Inc. | C-purine nucleoside analogs as inhibitors of rna-dependent rna viral polymerase |
WO2006012078A2 (en) | 2004-06-24 | 2006-02-02 | Merck & Co., Inc. | Nucleoside aryl phosphoramidates for the treatment of rna-dependent rna viral infection |
WO2004084796A3 (en) * | 2003-03-28 | 2006-04-06 | Pharmasset Ltd | Compounds for the treatment of flaviviridae infections |
US7034167B2 (en) | 2002-12-06 | 2006-04-25 | Merck & Co., Inc. | Process to ribofuranose sugar derivatives as intermediates to branched-chain nucleosides |
DE102004051804A1 (en) * | 2004-10-21 | 2006-04-27 | Max-Delbrück-Centrum Für Molekulare Medizin (Mdc) | Beta-L-N4-hydroxycytosine deoxynucleosides and their use as pharmaceutical agents for the prophylaxis or therapy of viral diseases |
US7094770B2 (en) | 2000-04-13 | 2006-08-22 | Pharmasset, Ltd. | 3′-or 2′-hydroxymethyl substituted nucleoside derivatives for treatment of hepatitis virus infections |
US7192936B2 (en) | 2002-06-28 | 2007-03-20 | Idenix Pharmaceuticals, Inc. | Modified 2′ and 3′-nucleoside prodrugs for treating Flaviviridae infections |
WO2007038860A2 (en) * | 2005-10-03 | 2007-04-12 | University Health Network | Odcase inhibitors as anti-virals and antibiotics |
WO2007144686A1 (en) * | 2005-03-09 | 2007-12-21 | Idenix (Cayman) Limited | Nucleosides with non-natural bases as anti-viral agents |
US7323449B2 (en) | 2002-07-24 | 2008-01-29 | Merck & Co., Inc. | Thionucleoside derivatives as inhibitors of RNA-dependent RNA viral polymerase |
US7339054B2 (en) | 2003-02-12 | 2008-03-04 | Merck & Co., Inc. | Process for preparing branched ribonucleosides from 1,2-anhydroribofuranose intermediates |
JP2008508296A (en) * | 2004-07-27 | 2008-03-21 | ギリアード サイエンシーズ, インコーポレイテッド | Imidazo [4,5-d] pyrimidines, their use and methods of preparation |
WO2008059130A1 (en) * | 2006-10-27 | 2008-05-22 | Universite Joseph Fourier (Grenoble 1) | Thionucleosides and pharmaceutical applications |
WO2008085508A2 (en) | 2007-01-05 | 2008-07-17 | Merck & Co., Inc. | Nucleoside aryl phosphoramidates for the treatment of rna-dependent rna viral infection |
WO2008106166A2 (en) | 2007-02-28 | 2008-09-04 | Conatus Pharmaceuticals, Inc. | Methods for the treatment of liver diseases using specified matrix metalloproteinase (mmp) inhibitors |
WO2009058102A1 (en) * | 2007-11-02 | 2009-05-07 | Agency For Science, Technology And Research | Methods and compounds for preventing and treating a tumour |
US7625875B2 (en) | 2002-06-28 | 2009-12-01 | Idenix Pharmaceuticals, Inc. | 2′ and 3′-nucleoside prodrugs for treating Flaviviridae infections |
WO2009115927A3 (en) * | 2008-03-18 | 2010-01-21 | Institut De Recherches Cliniques De Montreal | Nucleotide analogues with quaternary carbon stereogenic centers and methods of use |
US7666855B2 (en) | 2004-02-13 | 2010-02-23 | Metabasis Therapeutics, Inc. | 2′-C-methyl nucleoside derivatives |
WO2010082050A1 (en) | 2009-01-16 | 2010-07-22 | Istituto Di Ricerche Di Biologia Molecolare P. Angeletti S.P.A. | Macrocyclic and 7-aminoalkyl-substituted benzoxazocines for treatment of hepatitis c infections |
WO2010084115A2 (en) | 2009-01-20 | 2010-07-29 | Istituto Di Ricerche Di Biologia Molecolare P. Angeletti S.P.A. | Antiviral agents |
US7767660B2 (en) | 2006-12-20 | 2010-08-03 | Istituto Di Richerche Di Biologia Molecolare P. Angeletti Spa | Antiviral indoles |
US7772208B2 (en) | 2002-08-01 | 2010-08-10 | Pharmasset, Inc. | 2′,3′-dideoxynucleoside analogues for the treatment or prevention of Flaviviridae infections |
US7781422B2 (en) | 2006-12-20 | 2010-08-24 | Istituto Di Ricerche Di Biologia Molecolare P. Angeletti Spa | Antiviral indoles |
US20100227834A1 (en) * | 2006-08-11 | 2010-09-09 | RESprotech GmbH | Nucleosides for suppressing or reducing the development of resistance in cytostatic therapy |
WO2010101967A2 (en) | 2009-03-04 | 2010-09-10 | Idenix Pharmaceuticals, Inc. | Phosphothiophene and phosphothiazole hcv polymerase inhibitors |
WO2010115981A1 (en) | 2009-04-10 | 2010-10-14 | Novartis Ag | 7-azadispiro [3.0.4.1] decane-8-carboxamides as hepatitis c virus inhibitors |
WO2010116248A1 (en) | 2009-04-10 | 2010-10-14 | Novartis Ag | Organic compounds and their uses |
WO2010091386A3 (en) * | 2009-02-06 | 2010-12-09 | Rfs Pharma, Llc | Purine nucleoside monophosphate prodrugs for treatment of cancer and viral infections |
US7879797B2 (en) | 2005-05-02 | 2011-02-01 | Merck Sharp & Dohme Corp. | HCV NS3 protease inhibitors |
WO2011014882A1 (en) | 2009-07-31 | 2011-02-03 | Medtronic, Inc. | CONTINUOUS SUBCUTANEOUS ADMINISTRATION OF INTERFERON-α TO HEPATITIS C INFECTED PATIENTS |
WO2011014487A1 (en) | 2009-07-30 | 2011-02-03 | Merck Sharp & Dohme Corp. | Hepatitis c virus ns3 protease inhibitors |
WO2011017389A1 (en) | 2009-08-05 | 2011-02-10 | Idenix Pharmaceuticals, Inc. | Macrocyclic serine protease inhibitors useful against viral infections, particularly hcv |
US7902202B2 (en) | 2006-12-28 | 2011-03-08 | Idenix Pharmaceuticals, Inc. | Compounds and pharmaceutical compositions for the treatment of viral infections |
WO2011035250A1 (en) | 2009-09-21 | 2011-03-24 | Gilead Sciences, Inc. | Processes and intermediates for the preparation of 1'-substituted carba-nucleoside analogs |
WO2011035231A1 (en) | 2009-09-21 | 2011-03-24 | Gilead Sciences, Inc. | 2' -fluoro substituted carba-nucleoside analogs for antiviral treatment |
WO2008087558A3 (en) * | 2007-01-17 | 2011-04-21 | Institut De Recherches Cliniques De Montreal | Nucleoside and nucleotide analogues with quaternary carbon centers and methods of use |
WO2011058084A1 (en) | 2009-11-14 | 2011-05-19 | F. Hoffmann-La Roche Ag | Biomarkers for predicting rapid response to hcv treatment |
WO2011063076A1 (en) | 2009-11-19 | 2011-05-26 | Itherx Pharmaceuticals, Inc. | Methods of treating hepatitis c virus with oxoacetamide compounds |
WO2011067195A1 (en) | 2009-12-02 | 2011-06-09 | F. Hoffmann-La Roche Ag | Biomarkers for predicting sustained response to hcv treatment |
EP2332952A1 (en) | 2002-06-28 | 2011-06-15 | IDENIX Pharmaceuticals, Inc. | Modified 2' and 3'-nucleoside prodrugs for treating flaviridae infections |
WO2011075615A1 (en) | 2009-12-18 | 2011-06-23 | Idenix Pharmaceuticals, Inc. | 5,5-fused arylene or heteroarylene hepatitis c virus inhibitors |
US7973013B2 (en) | 2009-09-21 | 2011-07-05 | Gilead Sciences, Inc. | 2'-fluoro substituted carba-nucleoside analogs for antiviral treatment |
US7973040B2 (en) | 2008-07-22 | 2011-07-05 | Merck Sharp & Dohme Corp. | Macrocyclic quinoxaline compounds as HCV NS3 protease inhibitors |
US7989438B2 (en) | 2007-07-17 | 2011-08-02 | Istituto Di Ricerche Di Biologia Molecolare P. Angeletti Spa | Therapeutic compounds |
EP2351560A1 (en) | 2005-01-04 | 2011-08-03 | Novartis AG | Treatment Of HCV infections with FTY720 |
US8008264B2 (en) | 2008-04-23 | 2011-08-30 | Gilead Sciences, Inc. | 1′-substituted carba-nucleoside analogs for antiviral treatment |
US8012942B2 (en) | 2009-02-10 | 2011-09-06 | Gilead Sciences, Inc. | Carba-nucleoside analogs for antiviral treatment |
WO2011123586A1 (en) | 2010-04-01 | 2011-10-06 | Idenix Pharmaceuticals, Inc. | Compounds and pharmaceutical compositions for the treatment of viral infections |
WO2011150288A1 (en) | 2010-05-28 | 2011-12-01 | Gilead Sciences, Inc. | 1'-substituted-carba-nucleoside prodrugs for antiviral treatment |
US8093380B2 (en) | 2002-08-01 | 2012-01-10 | Pharmasset, Inc. | Compounds with the bicyclo[4.2.1]nonane system for the treatment of Flaviviridae infections |
US8101595B2 (en) | 2006-12-20 | 2012-01-24 | Istituto di Ricerche di Biologia Molecolare P. Angletti SpA | Antiviral indoles |
WO2012012465A1 (en) | 2010-07-19 | 2012-01-26 | Clarke, Michael, O'neil Hanrahan | Methods for the preparation of diasteromerically pure phosphoramidate prodrugs |
US8138164B2 (en) | 2006-10-24 | 2012-03-20 | Merck Sharp & Dohme Corp. | HCV NS3 protease inhibitors |
WO2012037038A1 (en) * | 2010-09-13 | 2012-03-22 | Gilead Sciences, Inc. | 2' -fluoro substituted carba-nucleoside analogs for antiviral treatment |
WO2012039791A1 (en) | 2010-09-20 | 2012-03-29 | Gilead Sciences, Inc. | 2' -fluoro substituted carba-nucleoside analogs for antiviral treatment |
WO2012048235A1 (en) | 2010-10-08 | 2012-04-12 | Novartis Ag | Vitamin e formulations of sulfamide ns3 inhibitors |
US8178520B2 (en) | 2006-05-15 | 2012-05-15 | Istituto Di Ricerche Di Biologia Molecolare P. Angeletti Spa | Macrocyclic compounds as antiviral agents |
WO2012080050A1 (en) | 2010-12-14 | 2012-06-21 | F. Hoffmann-La Roche Ag | Solid forms of a phenoxybenzenesulfonyl compound |
US8207177B2 (en) | 2006-02-02 | 2012-06-26 | Millennium Pharmaceuticals, Inc. | Inhibitors of E1 activating enzymes |
US8216999B2 (en) | 2005-07-20 | 2012-07-10 | Merck Sharp & Dohme Corp. | HCV NS3 protease inhibitors |
EP2476690A1 (en) | 2008-07-02 | 2012-07-18 | IDENIX Pharmaceuticals, Inc. | Compounds and pharmaceutical compositions for the treatment of viral infections |
CZ303327B6 (en) * | 2010-04-29 | 2012-08-01 | Univerzita Palackého v Olomouci | Substitution derivatives of N6-benzyladenosine-5?-monophosphate, methods of their preparation, their use for preparation of s medicament and therapeutic composition containing thereof |
WO2012109398A1 (en) | 2011-02-10 | 2012-08-16 | Idenix Pharmaceuticals, Inc. | Macrocyclic serine protease inhibitors, pharmaceutical compositions thereof, and their use for treating hcv infections |
CN102649788A (en) * | 2011-02-28 | 2012-08-29 | 四川大学 | Beta-L-2'-desoxy-thymin-nucleoside derivative, preparation method and purposes thereof |
US8278322B2 (en) | 2005-08-01 | 2012-10-02 | Merck Sharp & Dohme Corp. | HCV NS3 protease inhibitors |
WO2012135581A1 (en) | 2011-03-31 | 2012-10-04 | Idenix Pharmaceuticals, Inc. | Methods for treating drug-resistant hepatitis c virus infection with a 5,5-fused arylene or heteroarylene hepatitis c virus inhibitor |
WO2012142523A2 (en) | 2011-04-13 | 2012-10-18 | Gilead Sciences, Inc. | 1'-substituted pyrimidine n-nucleoside analogs for antiviral treatment |
EP2518079A2 (en) | 2006-04-11 | 2012-10-31 | Novartis AG | HCV/HIV inhibitors and their uses |
US8309540B2 (en) | 2006-10-24 | 2012-11-13 | Merck Sharp & Dohme Corp. | HCV NS3 protease inhibitors |
WO2012154321A1 (en) | 2011-03-31 | 2012-11-15 | Idenix Pharmaceuticals, Inc. | Compounds and pharmaceutical compositions for the treatment of viral infections |
US8314062B2 (en) | 2006-06-23 | 2012-11-20 | Instituto Di Ricerche Di Biologia Molecolare P. Angeletti S.P.A. | Macrocyclic compounds as antiviral agents |
GB2471806B (en) * | 2008-04-03 | 2012-12-19 | Spring Bank Pharmaceuticals Inc | Compositions and methods for treating viral infections |
US8349792B2 (en) | 2006-12-19 | 2013-01-08 | Cyclacel Limited | Combination comprising CNDAC (2′-cyano-2′-deoxy-N4-palmitoyl-1-beta-D-arabinofuranosyl-cytosine) and a cytotoxic agent |
US8377873B2 (en) | 2006-10-24 | 2013-02-19 | Merck Sharp & Dohme Corp. | HCV NS3 protease inhibitors |
US8377874B2 (en) | 2006-10-27 | 2013-02-19 | Merck Sharp & Dohme Corp. | HCV NS3 protease inhibitors |
WO2013039920A1 (en) | 2011-09-12 | 2013-03-21 | Idenix Pharmaceuticals, Inc. | Substituted carbonyloxymethylphosphoramidate compounds and pharmaceutical compositions for the treatment of viral infections |
WO2013039855A1 (en) | 2011-09-12 | 2013-03-21 | Idenix Pharmaceuticals, Inc. | Compounds and pharmaceutical compositions for the treatment of viral infections |
WO2013056046A1 (en) | 2011-10-14 | 2013-04-18 | Idenix Pharmaceuticals, Inc. | Substituted 3',5'-cyclic phosphates of purine nucleotide compounds and pharmaceutical compositions for the treatment of viral infections |
WO2013074386A2 (en) | 2011-11-15 | 2013-05-23 | Merck Sharp & Dohme Corp. | Hcv ns3 protease inhibitors |
US8455451B2 (en) | 2009-09-21 | 2013-06-04 | Gilead Sciences, Inc. | 2'-fluoro substituted carba-nucleoside analogs for antiviral treatment |
US8461107B2 (en) | 2008-04-28 | 2013-06-11 | Merck Sharp & Dohme Corp. | HCV NS3 protease inhibitors |
US8470870B2 (en) | 2008-03-27 | 2013-06-25 | Idenix Pharmaceuticals, Inc. | Solid forms of an anti-HIV phosphoindole compound |
US8481712B2 (en) | 2001-01-22 | 2013-07-09 | Merck Sharp & Dohme Corp. | Nucleoside derivatives as inhibitors of RNA-dependent RNA viral polymerase |
WO2013106344A1 (en) | 2012-01-12 | 2013-07-18 | Ligand Pharmaceuticals, Inc. | 2 '-c-methyl nucleosides containing a cyclic phosphate diester of 1, 3-propanediol (2-oxo-[1, 3, 2]-dioxaphosphorinane) at position 5' |
US8492539B2 (en) | 2004-09-14 | 2013-07-23 | Gilead Pharmasset Llc | Preparation of 2′-fluoro-2′-alkyl-substituted or other optionally substituted ribofuranosyl pyrimidines and purines and their derivatives |
US8530445B2 (en) | 2008-06-09 | 2013-09-10 | Cyclacel Limited | Combinations of sapacitabine or CNDAC with DNA methyltransferase inhibitors such as decitabine and procaine |
WO2013133927A1 (en) | 2012-02-13 | 2013-09-12 | Idenix Pharmaceuticals, Inc. | Pharmaceutical compositions of 2'-c-methyl-guanosine, 5'-[2-[(3-hydroxy-2,2-dimethyl-1-oxopropyl)thio]ethyl n-(phenylmethyl)phosphoramidate] |
WO2013138236A1 (en) * | 2012-03-13 | 2013-09-19 | Gilead Sciences , Inc. | 2'- substituted carba-nucleoside analogs for antiviral treatment |
US8551973B2 (en) | 2008-12-23 | 2013-10-08 | Gilead Pharmasset Llc | Nucleoside analogs |
US8580765B2 (en) | 2007-03-30 | 2013-11-12 | Gilead Pharmasset Llc | Nucleoside phosphoramidate prodrugs |
WO2013177188A1 (en) | 2012-05-22 | 2013-11-28 | Idenix Pharmaceuticals, Inc. | 3',5'-cyclic phosphoramidate prodrugs for hcv infection |
WO2013177219A1 (en) | 2012-05-22 | 2013-11-28 | Idenix Pharmaceuticals, Inc. | D-amino acid compounds for liver disease |
WO2013177195A1 (en) | 2012-05-22 | 2013-11-28 | Idenix Pharmaceuticals, Inc. | 3',5'-cyclic phosphate prodrugs for hcv infection |
WO2013179289A1 (en) | 2012-05-31 | 2013-12-05 | Bio-Lab Ltd. | Pyrazolotriazolyl nucleoside analogues and oligonucleotides comprising them |
US8629263B2 (en) | 2009-05-20 | 2014-01-14 | Gilead Pharmasset Llc | Nucleoside phosphoramidates |
US8633308B2 (en) | 2007-02-28 | 2014-01-21 | The Governors Of The University Of Alberta | Compounds for preventing or treating viral infections and methods of use thereof |
WO2014058801A1 (en) | 2012-10-08 | 2014-04-17 | Idenix Pharmaceuticals, Inc. | 2'-chloro nucleoside analogs for hcv infection |
WO2014063019A1 (en) | 2012-10-19 | 2014-04-24 | Idenix Pharmaceuticals, Inc. | Dinucleotide compounds for hcv infection |
WO2014066239A1 (en) | 2012-10-22 | 2014-05-01 | Idenix Pharmaceuticals, Inc. | 2',4'-bridged nucleosides for hcv infection |
US8716262B2 (en) | 2008-12-23 | 2014-05-06 | Gilead Pharmasset Llc | Nucleoside phosphoramidates |
US8716263B2 (en) | 2008-12-23 | 2014-05-06 | Gilead Pharmasset Llc | Synthesis of purine nucleosides |
WO2014070771A1 (en) * | 2012-10-29 | 2014-05-08 | Rfs Pharma, Llc | Pyrimidine nucleotides and their monophosphate prodrugs for treatment of viral infections and cancer |
WO2014078652A1 (en) * | 2012-11-16 | 2014-05-22 | Zs Genetics, Inc. | Heavy atom labeled nucleosides, nucleotides, and nucleic acid polymers, and uses thereof |
WO2014078436A1 (en) | 2012-11-14 | 2014-05-22 | Idenix Pharmaceuticals, Inc. | D-alanine ester of sp-nucleoside analog |
WO2014078427A1 (en) | 2012-11-14 | 2014-05-22 | Idenix Pharmaceuticals, Inc. | D-alanine ester of rp-nucleoside analog |
WO2014099941A1 (en) | 2012-12-19 | 2014-06-26 | Idenix Pharmaceuticals, Inc. | 4'-fluoro nucleosides for the treatment of hcv |
WO2014100498A1 (en) | 2012-12-21 | 2014-06-26 | Alios Biopharma, Inc. | Substituted nucleosides, nucleotides and analogs thereof |
WO2014123794A1 (en) | 2013-02-07 | 2014-08-14 | Merck Sharp & Dohme Corp. | Tetracyclic heterocycle compounds and methods of use thereof for the treatment of hepatitis c |
WO2014123795A2 (en) | 2013-02-07 | 2014-08-14 | Merck Sharp & Dohme Corp. | Tetracyclic heterocycle compounds and methods of use thereof for the treatment of hepatitis c |
US8815829B2 (en) | 2008-12-09 | 2014-08-26 | Rfs Pharma, Llc | 3′-azido purine nucleotide prodrugs for treatment of viral infections |
WO2014137926A1 (en) | 2013-03-04 | 2014-09-12 | Idenix Pharmaceuticals, Inc. | 3'-deoxy nucleosides for the treatment of hcv |
WO2014137930A1 (en) | 2013-03-04 | 2014-09-12 | Idenix Pharmaceuticals, Inc. | Thiophosphate nucleosides for the treatment of hcv |
WO2014148949A1 (en) | 2013-03-22 | 2014-09-25 | Асави, Ллс | Alkyl 2-{[(2r,3s,5r)-5-(4-amino-2-oxo-2н-pyrimidin-1-yl)-3-hydroxy- tetrahydro-furan-2-yl-methoxy]-phenoxy-phosphoryl-amino}-propionates, nucleoside inhibitors of hcv ns5b rna-polymerase, and methods for producing and use thereof |
WO2014165542A1 (en) | 2013-04-01 | 2014-10-09 | Idenix Pharmaceuticals, Inc. | 2',4'-fluoro nucleosides for the treatment of hcv |
US8859756B2 (en) | 2010-03-31 | 2014-10-14 | Gilead Pharmasset Llc | Stereoselective synthesis of phosphorus containing actives |
EP2794627A1 (en) * | 2011-12-22 | 2014-10-29 | Alios Biopharma, Inc. | Substituted nucleosides, nucleotides and analogs thereof |
US8889159B2 (en) | 2011-11-29 | 2014-11-18 | Gilead Pharmasset Llc | Compositions and methods for treating hepatitis C virus |
WO2014197578A1 (en) | 2013-06-05 | 2014-12-11 | Idenix Pharmaceuticals, Inc. | 1',4'-thio nucleosides for the treatment of hcv |
US8927569B2 (en) | 2007-07-19 | 2015-01-06 | Merck Sharp & Dohme Corp. | Macrocyclic compounds as antiviral agents |
WO2015017713A1 (en) | 2013-08-01 | 2015-02-05 | Idenix Pharmaceuticals, Inc. | D-amino acid phosphoramidate pronucleotides of halogeno pyrimidine compounds for liver disease |
WO2015034420A1 (en) * | 2013-09-04 | 2015-03-12 | Medivir Ab | Hcv polymerase inhibitors |
EP2848624A1 (en) * | 2007-11-20 | 2015-03-18 | Gilead Pharmasset LLC | 2',4'-substituted nucleosides as antiviral agents |
WO2015042375A1 (en) | 2013-09-20 | 2015-03-26 | Idenix Pharmaceuticals, Inc. | Hepatitis c virus inhibitors |
WO2015061683A1 (en) | 2013-10-25 | 2015-04-30 | Idenix Pharmaceuticals, Inc. | D-amino acid phosphoramidate and d-alanine thiophosphoramidate pronucleotides of nucleoside compounds useful for the treatment of hcv |
WO2015066370A1 (en) | 2013-11-01 | 2015-05-07 | Idenix Pharmaceuticals, Inc. | D-alanine phosphoramidate pronucleotides of 2'-methyl 2'-fluoro guanosine nucleoside compounds for the treatment of hcv |
WO2015069939A1 (en) * | 2013-11-11 | 2015-05-14 | Gilead Sciences, Inc. | Pyrrolo [1,2,f] [1,2,4] triazines useful for treating respiratory syncitial virus infections |
WO2015081297A1 (en) | 2013-11-27 | 2015-06-04 | Idenix Pharmaceuticals, Inc. | 2'-dichloro and 2'-fluoro-2'-chloro nucleoside analogues for hcv infection |
US9061041B2 (en) | 2011-04-13 | 2015-06-23 | Merck Sharp & Dohme Corp. | 2′-substituted nucleoside derivatives and methods of use thereof for the treatment of viral diseases |
WO2015095419A1 (en) | 2013-12-18 | 2015-06-25 | Idenix Pharmaceuticals, Inc. | 4'-or nucleosides for the treatment of hcv |
WO2015134561A1 (en) | 2014-03-05 | 2015-09-11 | Idenix Pharmaceuticals, Inc. | Pharmaceutical compositions comprising a 5,5-fused heteroarylene flaviviridae inhibitor and their use for treating or preventing flaviviridae infection |
WO2015134560A1 (en) | 2014-03-05 | 2015-09-11 | Idenix Pharmaceuticals, Inc. | Solid forms of a flaviviridae virus inhibitor compound and salts thereof |
US9139833B2 (en) | 2002-07-26 | 2015-09-22 | Arrowhead Research Corporation | Modified small interfering RNA molecules and methods of use |
US9150603B2 (en) | 2011-04-13 | 2015-10-06 | Merck Sharp & Dohme Corp. | 2′-cyano substituted nucleoside derivatives and methods of use thereof useful for the treatment of viral diseases |
US9156872B2 (en) | 2011-04-13 | 2015-10-13 | Merck Sharp & Dohme Corp. | 2′-azido substituted nucleoside derivatives and methods of use thereof for the treatment of viral diseases |
WO2015161137A1 (en) | 2014-04-16 | 2015-10-22 | Idenix Pharmaceuticals, Inc. | 3'-substituted methyl or alkynyl nucleosides for the treatment of hcv |
US9187482B2 (en) | 2009-05-14 | 2015-11-17 | Millennium Pharmaceuticals, Inc. | Hydrochloride salt of((1S,2S,4R)-4-{4-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}-2-hydroxycyclopentyl)methyl sulfamate |
EP2827875A4 (en) * | 2012-03-21 | 2015-12-02 | Alios Biopharma Inc | Substituted nucleosides, nucleotides and analogs thereof |
US9216979B2 (en) | 2009-10-16 | 2015-12-22 | Melinta Therapeutics, Inc. | Antimicrobial compounds and methods of making and using the same |
US9284342B2 (en) | 2009-05-20 | 2016-03-15 | Gilead Pharmasset Llc | Nucleoside phosphoramidates |
WO2016038562A1 (en) * | 2014-09-11 | 2016-03-17 | Malaysian Institute Of Pharmaceuticals And Nutraceuticals | Thioguanine derivatives |
US9408863B2 (en) | 2011-07-13 | 2016-08-09 | Merck Sharp & Dohme Corp. | 5′-substituted nucleoside analogs and methods of use thereof for the treatment of viral diseases |
US9416154B2 (en) | 2011-07-13 | 2016-08-16 | Merck Sharp & Dohme Corp. | 5′-substituted nucleoside derivatives and methods of use thereof for the treatment of viral diseases |
WO2016134057A1 (en) * | 2015-02-18 | 2016-08-25 | Abbvie Inc. | Anti-viral compounds |
US9447132B2 (en) | 2013-04-12 | 2016-09-20 | Achillion Pharmaceuticals, Inc. | Highly active nucleoside derivative for the treatment of HCV |
US9573962B2 (en) | 2009-10-16 | 2017-02-21 | Melinta Therapeutics, Inc. | Antimicrobial compounds and methods of making and using the same |
KR20170042643A (en) * | 2014-08-21 | 2017-04-19 | 길리애드 사이언시즈, 인코포레이티드 | 2'-chloro aminopyrimidinone and pyrimidine dione nucleosides |
US9676797B2 (en) | 2015-09-02 | 2017-06-13 | Abbvie Inc. | Anti-viral compounds |
US9724360B2 (en) | 2014-10-29 | 2017-08-08 | Gilead Sciences, Inc. | Methods for treating Filoviridae virus infections |
US9738661B2 (en) | 2006-10-27 | 2017-08-22 | Merck Sharp & Dohme Corp. | HCV NS3 protease inhibitors |
US9771332B2 (en) | 2015-05-05 | 2017-09-26 | Pfizer Inc. | 2-thiopyrimidinones |
US9828410B2 (en) | 2015-03-06 | 2017-11-28 | Atea Pharmaceuticals, Inc. | β-D-2′-deoxy-2′-α-fluoro-2′-β-C-substituted-2-modified-N6-substituted purine nucleotides for HCV treatment |
US9873673B2 (en) | 2011-11-11 | 2018-01-23 | Pfizer Inc. | 2-thiopyrimidinones |
US9937183B2 (en) | 2013-09-09 | 2018-04-10 | Melinta Therapeutics, Inc. | Antimicrobial compounds and methods of making and using the same |
US10039779B2 (en) | 2013-01-31 | 2018-08-07 | Gilead Pharmasset Llc | Combination formulation of two antiviral compounds |
US10065958B2 (en) | 2010-07-22 | 2018-09-04 | Gilead Sciences, Inc. | Methods and compounds for treating Paramyxoviridae virus infections |
US10106543B2 (en) | 2013-09-09 | 2018-10-23 | Melinta Therapeutics, Inc. | Antimicrobial compounds and methods of making and using the same |
US10202412B2 (en) | 2016-07-08 | 2019-02-12 | Atea Pharmaceuticals, Inc. | β-D-2′-deoxy-2′-substituted-4′-substituted-2-substituted-N6-substituted-6-aminopurinenucleotides for the treatment of paramyxovirus and orthomyxovirus infections |
US10226478B2 (en) | 2011-04-14 | 2019-03-12 | Cyclacel Limited | Dosage regimen for sapacitabine and decitabine in combination for treating acute myeloid leukemia |
US10251904B2 (en) | 2015-09-16 | 2019-04-09 | Gilead Sciences, Inc. | Methods for treating arenaviridae and coronaviridae virus infections |
US10307439B2 (en) | 2014-06-24 | 2019-06-04 | Alios Biopharma, Inc. | Substituted nucleosides, nucleotides and analogs thereof |
US10456414B2 (en) | 2011-09-16 | 2019-10-29 | Gilead Pharmasset Llc | Methods for treating HCV |
US10485815B2 (en) | 2012-03-21 | 2019-11-26 | Alios Biopharma, Inc. | Substituted nucleosides, nucleotides and analogs thereof |
US10675296B2 (en) | 2017-07-11 | 2020-06-09 | Gilead Sciences, Inc. | Compositions comprising an RNA polymerase inhibitor and cyclodextrin for treating viral infections |
US10682368B2 (en) | 2017-03-14 | 2020-06-16 | Gilead Sciences, Inc. | Methods of treating feline coronavirus infections |
USRE48171E1 (en) | 2012-03-21 | 2020-08-25 | Janssen Biopharma, Inc. | Substituted nucleosides, nucleotides and analogs thereof |
US10836787B2 (en) | 2017-05-01 | 2020-11-17 | Gilead Sciences, Inc. | Crystalline forms of (S)-2-ethylbutyl 2-(((S)-(((2R,3S,4R,5R)-5- (4-aminopyrrolo[2,1-f] [1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy) phosphoryl)amino)propanoate |
EP3750544A2 (en) | 2011-11-30 | 2020-12-16 | Emory University | Jak inhibitors for use in the prevention or treatment of viral infection |
US10874687B1 (en) | 2020-02-27 | 2020-12-29 | Atea Pharmaceuticals, Inc. | Highly active compounds against COVID-19 |
US10946033B2 (en) | 2016-09-07 | 2021-03-16 | Atea Pharmaceuticals, Inc. | 2′-substituted-N6-substituted purine nucleotides for RNA virus treatment |
US10947237B2 (en) | 2015-03-11 | 2021-03-16 | BioVersys AG | Antimicrobial compounds and methods of making and using the same |
US11116783B2 (en) | 2013-08-27 | 2021-09-14 | Gilead Pharmasset Llc | Combination formulation of two antiviral compounds |
WO2021236859A1 (en) * | 2020-05-22 | 2021-11-25 | Merck Sharp & Dohme Corp. | Synthesis of fluorinated nucleotides |
US11331331B2 (en) | 2017-12-07 | 2022-05-17 | Emory University | N4-hydroxycytidine and derivatives and anti-viral uses related thereto |
US11491169B2 (en) | 2020-05-29 | 2022-11-08 | Gilead Sciences, Inc. | Remdesivir treatment methods |
WO2022245814A1 (en) * | 2021-05-17 | 2022-11-24 | Rome Therapeutics, Inc. | Methods of treating medical conditions and inhibiting line1 reverse transcriptase using a substituted 4-fluoro-2,5-dihydrofuranyl phosphonic acid or related compound |
US11613553B2 (en) | 2020-03-12 | 2023-03-28 | Gilead Sciences, Inc. | Methods of preparing 1′-cyano nucleosides |
US11628181B2 (en) | 2014-12-26 | 2023-04-18 | Emory University | N4-hydroxycytidine and derivatives and anti-viral uses related thereto |
US11660307B2 (en) | 2020-01-27 | 2023-05-30 | Gilead Sciences, Inc. | Methods for treating SARS CoV-2 infections |
US11690860B2 (en) | 2018-04-10 | 2023-07-04 | Atea Pharmaceuticals, Inc. | Treatment of HCV infected patients with cirrhosis |
US11701372B2 (en) | 2020-04-06 | 2023-07-18 | Gilead Sciences, Inc. | Inhalation formulations of 1'-cyano substituted carba-nucleoside analogs |
US11780844B2 (en) | 2022-03-02 | 2023-10-10 | Gilead Sciences, Inc. | Compounds and methods for treatment of viral infections |
US11814406B2 (en) | 2020-08-27 | 2023-11-14 | Gilead Sciences, Inc. | Compounds and methods for treatment of viral infections |
US11865132B2 (en) | 2021-12-16 | 2024-01-09 | Ascletis Bioscience Co., Ltd. | Nucleoside derivatives and methods of use thereof |
US11939347B2 (en) | 2020-06-24 | 2024-03-26 | Gilead Sciences, Inc. | 1′-cyano nucleoside analogs and uses thereof |
Families Citing this family (63)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
ES2402597T3 (en) | 2000-10-18 | 2013-05-07 | Gilead Pharmasset Llc | Modified nucleosides for the treatment of viral infections and abnormal cell proliferation |
US7022680B2 (en) * | 2002-05-30 | 2006-04-04 | Albert Einstein College Of Medicine Of Yeshiva University | Inhibitors of ADP-ribosyl transferases, cyclases, and hydrolases |
CN101172993A (en) * | 2002-06-28 | 2008-05-07 | 埃迪尼克斯(开曼)有限公司 | 2'-c-methyl-3'-o-l-valine ester ribofuranosyl cytidine for treatment of flaviviridae infections |
RU2005121904A (en) * | 2002-12-12 | 2006-01-20 | Айденикс (Кайман) Лимитед (Ky) | METHOD FOR PRODUCING 2`-BRANCHED NUCLEOSIDES |
NZ540913A (en) * | 2002-12-23 | 2008-02-29 | Idenix Cayman Ltd | Process for the production of 3'-nucleoside prodrugs |
WO2005018330A1 (en) * | 2003-08-18 | 2005-03-03 | Pharmasset, Inc. | Dosing regimen for flaviviridae therapy |
US7582428B2 (en) * | 2003-08-22 | 2009-09-01 | The Board Of Trustees Of The Leland Stanford Junior University | Methods and compositions for identifying anti-HCV agents |
US20050131224A1 (en) * | 2003-12-15 | 2005-06-16 | Cti Pet Systems, Inc. | Method for preparing radiolabeled thymidine |
US7160537B2 (en) | 2003-12-15 | 2007-01-09 | Siemens Medical Solutions Usa, Inc. | Method for preparing radiolabeled thymidine having low chromophoric byproducts |
AU2005256963A1 (en) * | 2004-06-23 | 2006-01-05 | Centre National De La Recherche Scientifique | 5-aza-7-deazapurine derivatives for treating infections with flaviviridae |
EP1849786A4 (en) * | 2005-01-25 | 2011-03-16 | Ajinomoto Kk | Method for producing nucleoside derivative |
WO2006130217A2 (en) * | 2005-04-01 | 2006-12-07 | The Regents Of The University Of California | Substituted phosphate esters of nucleoside phosphonates |
US20090270431A1 (en) * | 2005-10-19 | 2009-10-29 | The University Of Georgia Research Foundation | Cyclopentenol Nucleoside Compounds Intermediates for their Synthesis and Methods of Treating Viral Infections |
GB0523041D0 (en) * | 2005-11-11 | 2005-12-21 | Cyclacel Ltd | Combination |
WO2007075876A2 (en) * | 2005-12-23 | 2007-07-05 | Idenix Pharmaceuticals, Inc. | Process for preparing a synthetic intermediate for preparation of branched nucleosides |
HUP0600042A3 (en) * | 2006-01-19 | 2012-12-28 | Debreceni Egyetem | New medical use of thiolated pyrimidine-mononucleotides and -nucleosides |
US7655419B2 (en) * | 2006-08-25 | 2010-02-02 | The Board Of Trustees Of The Leland Stanford Junior University | Methods and compositions for identifying anti-HCV agents |
WO2008118852A1 (en) * | 2007-03-23 | 2008-10-02 | Southern Research Institute | Method for treating and preventing arthritis |
WO2008124157A1 (en) * | 2007-04-10 | 2008-10-16 | University Of Georgia Research Foundation, Inc. | Carbocyclic compounds and methods for treating emerging diseases, including influenza and venezuela equine encephalitis virus |
WO2009005615A1 (en) * | 2007-06-27 | 2009-01-08 | The Board Of Trustees Of The Leland Stanford Junior University | Methods and compositions for identifying agents that inhibit an ns4b-mediated neoplastic cellular phenotype of hcv infected cells |
WO2010002877A2 (en) | 2008-07-03 | 2010-01-07 | Biota Scientific Management | Bycyclic nucleosides and nucleotides as therapeutic agents |
WO2010090723A2 (en) * | 2009-02-04 | 2010-08-12 | University Of Georgia Research Foundation, Inc. | Methods of inhibiting fibrogenesis and treating fibrotic disease |
TWI612048B (en) * | 2009-10-16 | 2018-01-21 | 梅林塔療法公司 | Antimicrobial compounds and methods of making and using the same |
ES2437933T3 (en) * | 2010-01-28 | 2014-01-15 | F. Hoffmann-La Roche Ag | 4'-azido-nucleosides as anti-HCV compounds |
TW201211614A (en) | 2010-09-10 | 2012-03-16 | Genius Electronic Optical Co Ltd | Imaging lens composed of four lenses and electronic device using the same |
TW201242974A (en) | 2010-11-30 | 2012-11-01 | Gilead Pharmasset Llc | Compounds |
HUE029038T2 (en) | 2012-05-25 | 2017-01-30 | Janssen Sciences Ireland Uc | Uracyl spirooxetane nucleosides |
WO2014052638A1 (en) | 2012-09-27 | 2014-04-03 | Idenix Pharmaceuticals, Inc. | Esters and malonates of sate prodrugs |
CN102924552B (en) * | 2012-11-14 | 2014-09-10 | 南京中医药大学 | Compound with anti-herpes-virus function |
GEP201706757B (en) | 2012-12-21 | 2017-10-25 | Alios Biopharma Inc | Substituted nucleosides, nucleotides and analogs thereof |
CN102977170B (en) * | 2012-12-26 | 2015-04-22 | 南京亚东启天药业有限公司 | Synthesis process for industrial production of capecitabine intermediate |
US10034893B2 (en) | 2013-02-01 | 2018-07-31 | Enanta Pharmaceuticals, Inc. | 5, 6-D2 uridine nucleoside/tide derivatives |
EP2970357A1 (en) | 2013-03-13 | 2016-01-20 | IDENIX Pharmaceuticals, Inc. | Amino acid phosphoramidate pronucleotides of 2'-cyano, azido and amino nucleosides for the treatment of hcv |
CN103709221B (en) * | 2013-12-05 | 2016-04-27 | 湖南科源生物制品有限公司 | A kind of preparation method of cordycepin |
EP3102215B1 (en) * | 2014-02-06 | 2021-06-16 | Riboscience LLC | 4'-difluoromethyl substituted nucleoside derivatives as inhibitors of influenza rna replication |
WO2015123352A1 (en) | 2014-02-13 | 2015-08-20 | Ligand Pharmaceuticals, Inc. | Prodrug compounds and their uses |
CN103819524B (en) * | 2014-03-04 | 2016-04-13 | 郑州格然林医药科技有限公司 | 3 '-fluorine substituted purin nucleoside analog, its preparation method and application thereof |
JP2017520545A (en) | 2014-07-02 | 2017-07-27 | リガンド・ファーマシューティカルズ・インコーポレイテッド | Prodrug compounds and their use |
CN104961787B (en) * | 2014-07-10 | 2020-06-26 | 深圳松乐生物科技有限公司 | Synthetic method of cordycepin |
US9657048B2 (en) | 2014-08-04 | 2017-05-23 | Auburn University | Enantiomers of the 1′,6′-isomer of neplanocin A |
US9675632B2 (en) | 2014-08-26 | 2017-06-13 | Enanta Pharmaceuticals, Inc. | Nucleoside and nucleotide derivatives |
WO2016073756A1 (en) | 2014-11-06 | 2016-05-12 | Enanta Pharmaceuticals, Inc. | Deuterated nucleoside/tide derivatives |
US9732110B2 (en) | 2014-12-05 | 2017-08-15 | Enanta Pharmaceuticals, Inc. | Nucleoside and nucleotide derivatives |
WO2016180691A1 (en) * | 2015-05-08 | 2016-11-17 | F. Hoffmann-La Roche Ag | Novel oxathiolane carboxylic acids and derivatives for the treatment and prophylaxis of virus infection |
CN105566304B (en) * | 2016-01-13 | 2019-04-30 | 大连大学 | Sulfur-bearing uridine anticancer compound and its intermediate and preparation method |
WO2017156380A1 (en) * | 2016-03-10 | 2017-09-14 | Emory University | N4-hydroxycytidine and derivatives and anti-viral uses related thereto |
EP3426671A4 (en) * | 2016-03-11 | 2019-11-20 | Spring Bank Pharmaceuticals, Inc. | Compounds and compositions for the treatment of infections |
KR102592899B1 (en) | 2017-02-01 | 2023-10-24 | 아테아 파마슈티컬즈, 인크. | Nucleotide hemi-sulfate salt for the treatment of hepatitis c virus |
CN107033205B (en) * | 2017-06-12 | 2020-05-19 | 上海兆维科技发展有限公司 | Preparation method of 3' -deoxyuridine |
CN107383011B (en) * | 2017-08-01 | 2019-05-10 | 深圳百奥捷生物科技有限公司 | A kind of antiviral alkaloid and preparation method thereof being isolated from Folium Forsythia radix scutellariae |
CN107253951B (en) * | 2017-08-01 | 2019-05-10 | 深圳百奥捷生物科技有限公司 | A kind of purine alkaloid and its application as anti-RSV virus drugs |
KR200486741Y1 (en) | 2017-08-24 | 2018-06-27 | 류제웅 | Apparatus For treatment or relaxation For Slipped Disc |
US11059824B2 (en) * | 2018-05-25 | 2021-07-13 | Primmune Therapeutics, Inc. | Substituted purines as TLR7 agonists |
CN108676048B (en) * | 2018-06-04 | 2021-04-27 | 上海兆维科技发展有限公司 | Preparation method of cordycepin |
US11446303B2 (en) * | 2019-06-21 | 2022-09-20 | Tosk, Inc. | Uridine phosphorylase (UPase) inhibitors for treatment of liver conditions |
CN115427063A (en) | 2019-11-26 | 2022-12-02 | 普利缪尼治疗学股份有限公司 | TLR7 agonists |
CN111675660B (en) * | 2020-05-07 | 2021-12-10 | 奥锐特药业股份有限公司 | Preparation method for synthesizing palbociclib intermediate and method for synthesizing palbociclib |
CN112608357B (en) * | 2020-12-21 | 2022-12-09 | 杭州科巢生物科技有限公司 | Preparation method of antiviral drug Molnbupiravir |
WO2022218274A1 (en) * | 2021-04-15 | 2022-10-20 | 中国科学院上海药物研究所 | Nucleoside analog and use thereof |
CN113307833B (en) * | 2021-06-16 | 2022-07-05 | 苏州立新制药有限公司 | Preparation method of N4-hydroxycytidine |
CN113735927A (en) * | 2021-10-18 | 2021-12-03 | 厦门一先药业有限公司 | Nucleotide analogue and preparation method and application thereof |
KR20230001778U (en) | 2022-03-02 | 2023-09-11 | 류제웅 | Sleeping Waste Belt For Improving Cervical Disk Problem |
CN115536710B (en) * | 2022-10-18 | 2024-04-16 | 南京工业大学 | Preparation method of high-quality cytidine sulfate crystal |
Family Cites Families (98)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4232154A (en) * | 1977-12-13 | 1980-11-04 | United States Of America | Carbocyclic analogs of cytosine nucleosides exhibiting antiviral and antineoplasticactivity |
US4211773A (en) * | 1978-10-02 | 1980-07-08 | Sloan Kettering Institute For Cancer Research | 5-Substituted 1-(2'-Deoxy-2'-substituted-β-D-arabinofuranosyl)pyrimidine nucleosides |
JPS608270A (en) * | 1983-06-29 | 1985-01-17 | Yoshitomi Pharmaceut Ind Ltd | Novel nucleoside having cyclopentene ring |
US4666892A (en) * | 1984-03-06 | 1987-05-19 | Sloan-Kettering Memorial Cancer Center | Method and composition for hepatitis treatment with pyrimidine nucleoside compounds |
JPS6187673A (en) * | 1984-10-06 | 1986-05-06 | Yoshitomi Pharmaceut Ind Ltd | Acylcytosine derivative |
JPS61130299A (en) * | 1984-11-30 | 1986-06-18 | Daikin Ind Ltd | Production of 5-fluorocytidine compound hydrochloride |
US5223263A (en) | 1988-07-07 | 1993-06-29 | Vical, Inc. | Liponucleotide-containing liposomes |
US4975434A (en) * | 1986-05-27 | 1990-12-04 | The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services | Antiviral and anticancer cyclopentenyl cytosine |
US4968690A (en) * | 1986-05-27 | 1990-11-06 | United States Government As Represented By The Secretary Of The Dept. Of Health And Human Services | 3-deazaneplanocin, intermediates for it, and antiviral composition and method of treatment using it |
US5446029A (en) * | 1986-07-04 | 1995-08-29 | Medivir Ab | Anti-retroviral activity of 2',3'-dideoxy-3'-fluoronucleosides |
EP0277599A3 (en) * | 1987-01-30 | 1990-05-09 | Asahi Glass Company Ltd. | Fluorine containing cyclopentane derivatives and processes for their production |
SE8701605D0 (en) | 1987-04-16 | 1987-04-16 | Astra Ab | NOVEL MEDICINAL COMPOUNDS |
GB8712115D0 (en) | 1987-05-22 | 1987-06-24 | Hoffmann La Roche | Pyrimidine derivatives |
US4835104A (en) * | 1987-06-16 | 1989-05-30 | Ajinomoto Co., Inc., Patent & Licensing Department | Process for producing and purifying 2',3'-dideoxynucleosides, and process for producing 2',3'-dideoxy-2',3'-didehydronucleosides |
JPS6442499A (en) * | 1987-08-10 | 1989-02-14 | Yoshitomi Pharmaceutical | Cytosine derivative of racemic type |
IL87646A (en) * | 1987-09-03 | 1994-07-31 | Sloan Kettering Inst Cancer | Composition for treating hepatitis virus infections comprising 1-(2'-deoxy-2'-fluoro-beta-d-arabino-furanosyl)-5-ethyl-uracil |
US5246924A (en) * | 1987-09-03 | 1993-09-21 | Sloan-Kettering Institute For Cancer Research | Method for treating hepatitis B virus infections using 1-(2'-deoxy-2'-fluoro-beta-D-arabinofuranosyl)-5-ethyluracil |
AU2526188A (en) | 1987-09-22 | 1989-04-18 | Regents Of The University Of California, The | Liposomal nucleoside analogues for treating aids |
US4908440A (en) | 1987-11-12 | 1990-03-13 | Bristol Myers Company | 2',3'-dideoxy-2'-fluoroarabinopyrimidine nucleosides |
SE8802173D0 (en) | 1988-06-10 | 1988-06-10 | Astra Ab | PYRIMIDINE DERIVATIVES |
SE8802687D0 (en) | 1988-07-20 | 1988-07-20 | Astra Ab | NUCLEOSIDE DERIVATIVES |
US5035878A (en) | 1988-09-12 | 1991-07-30 | University Of Rochester | Use of dithiocarbamates to counteract myelosuppression |
US5034518A (en) * | 1989-05-23 | 1991-07-23 | Southern Research Institute | 2-fluoro-9-(2-deoxy-2-fluoro-β-D-arabinofuranosyl) adenine nucleosides |
US5411947A (en) | 1989-06-28 | 1995-05-02 | Vestar, Inc. | Method of converting a drug to an orally available form by covalently bonding a lipid to the drug |
US5194654A (en) | 1989-11-22 | 1993-03-16 | Vical, Inc. | Lipid derivatives of phosphonoacids for liposomal incorporation and method of use |
DD293498A5 (en) | 1989-07-20 | 1991-09-05 | Zi Fuer Molekularbiologie Der Adw,De | METHOD FOR PRODUCING A MEDIUM FOR THE TREATMENT OR PROPHYLAXIS OF HEPATITE INFECTIONS IN HUMANS AND ANIMALS |
GB8920534D0 (en) | 1989-09-11 | 1989-10-25 | Wellcome Found | Antiviral compounds |
US5886162A (en) * | 1989-11-03 | 1999-03-23 | Research Foundation Of State University Of New York | Lipophilic diakylaminomethylene prodrug derivatives for the inhibition of replication of viruses |
US5463092A (en) | 1989-11-22 | 1995-10-31 | Vestar, Inc. | Lipid derivatives of phosphonacids for liposomal incorporation and method of use |
US5026687A (en) | 1990-01-03 | 1991-06-25 | The United States Of America As Represented By The Department Of Health And Human Services | Treatment of human retroviral infections with 2',3'-dideoxyinosine alone and in combination with other antiviral compounds |
US5204466A (en) | 1990-02-01 | 1993-04-20 | Emory University | Method and compositions for the synthesis of bch-189 and related compounds |
GB9007569D0 (en) * | 1990-04-04 | 1990-05-30 | Nycomed As | Carbo-nucleoside derivatives |
WO1991016920A1 (en) | 1990-05-07 | 1991-11-14 | Vical, Inc. | Lipid prodrugs of salicylate and nonsteroidal anti-inflammatory drugs |
AU7623991A (en) | 1990-05-17 | 1991-11-21 | Syntex (U.S.A.) Inc. | Antiviral agents |
US5192749A (en) * | 1990-05-21 | 1993-03-09 | Syntex (U.S.A.) Inc. | 4'-substituted nucleosides |
EP0531452A4 (en) | 1990-05-29 | 1993-06-09 | Vical, Inc. | Synthesis of glycerol di- and triphosphate derivatives |
WO1991019721A1 (en) | 1990-06-13 | 1991-12-26 | Arnold Glazier | Phosphorous produgs |
US5149794A (en) | 1990-11-01 | 1992-09-22 | State Of Oregon | Covalent lipid-drug conjugates for drug targeting |
US5256641A (en) | 1990-11-01 | 1993-10-26 | State Of Oregon | Covalent polar lipid-peptide conjugates for immunological targeting |
US5543389A (en) | 1990-11-01 | 1996-08-06 | State Of Oregon, Acting By And Through The Oregon State Board Of Higher Education On Behalf Of The Oregon Health Sciences University, A Non Profit Organization | Covalent polar lipid-peptide conjugates for use in salves |
US5543390A (en) | 1990-11-01 | 1996-08-06 | State Of Oregon, Acting By And Through The Oregon State Board Of Higher Education, Acting For And On Behalf Of The Oregon Health Sciences University | Covalent microparticle-drug conjugates for biological targeting |
IT1246983B (en) | 1990-11-13 | 1994-12-12 | Consiglio Nazionale Ricerche | L-2'-DESOXYURIDINE AND PHARMACEUTICAL COMPOSITIONS THAT CONTAIN IT. |
NZ250842A (en) | 1991-02-22 | 1996-03-26 | Univ Emory | Resolution of a racemic mixture of nucleoside enantiomers such as 2-hydroxymethyl-5-(5-fluorocytosin-1-yl)-1,3-oxathiolane (ftc) |
WO1993000910A1 (en) | 1991-07-12 | 1993-01-21 | Vical, Inc. | Antiviral liponucleosides: treatment of hepatitis b |
US5554728A (en) | 1991-07-23 | 1996-09-10 | Nexstar Pharmaceuticals, Inc. | Lipid conjugates of therapeutic peptides and protease inhibitors |
MY111746A (en) * | 1992-07-02 | 2000-12-30 | The Wellcome Foundation Ltd | Therapeutic nucleosides. |
US6080791A (en) * | 1992-07-24 | 2000-06-27 | Seres Laboratories, Inc. | Method of treating a viral condition by inhibiting membrane fusion |
JPH06107548A (en) | 1992-08-10 | 1994-04-19 | Nippon Kayaku Co Ltd | Inhibitor for metastasis of cancer to liver and medicine for improving hepatic cancer |
JPH0665211A (en) | 1992-08-21 | 1994-03-08 | Yoshitomi Pharmaceut Ind Ltd | Cyclopentane nucleoside compound |
JPH0680688A (en) * | 1992-09-03 | 1994-03-22 | Asahi Breweries Ltd | 4'-methylnucleoside derivative |
US6174868B1 (en) | 1992-09-10 | 2001-01-16 | Isis Pharmaceuticals, Inc. | Compositions and methods for treatment of hepatitis C virus-associated diseases |
WO1994014831A1 (en) | 1992-12-18 | 1994-07-07 | The University Of Alberta | Dihydropyrimidine nucleosides with antiviral properties |
US5512671A (en) * | 1993-02-16 | 1996-04-30 | Wake Forest University | Ether lipid-nucleoside covalent conjugates |
EP0686043B1 (en) | 1993-02-24 | 1999-06-23 | WANG, Jui, H. | Compositions and methods of application of reactive antiviral polymers |
JPH08510236A (en) | 1993-05-12 | 1996-10-29 | カール ワイ. ホステトラー | Acyclovir derivative for topical use |
US5654286A (en) | 1993-05-12 | 1997-08-05 | Hostetler; Karl Y. | Nucleotides for topical treatment of psoriasis, and methods for using same |
US5846964A (en) | 1993-07-19 | 1998-12-08 | Tokyo Tanabe Company Limited | Hepatitis C virus proliferation inhibitor |
JP3487441B2 (en) | 1993-09-22 | 2004-01-19 | 株式会社デンソー | Method for producing active material for lithium secondary battery |
US5587362A (en) * | 1994-01-28 | 1996-12-24 | Univ. Of Ga Research Foundation | L-nucleosides |
DE4432623A1 (en) | 1994-09-14 | 1996-03-21 | Huels Chemische Werke Ag | Process for bleaching aqueous surfactant solutions |
US5696277A (en) | 1994-11-15 | 1997-12-09 | Karl Y. Hostetler | Antiviral prodrugs |
US5703058A (en) * | 1995-01-27 | 1997-12-30 | Emory University | Compositions containing 5-fluoro-2',3'-didehydro-2',3'-dideoxycytidine or a mono-, di-, or triphosphate thereof and a second antiviral agent |
US5808040A (en) * | 1995-01-30 | 1998-09-15 | Yale University | L-nucleosides incorporated into polymeric structure for stabilization of oligonucleotides |
JP3786447B2 (en) | 1995-03-31 | 2006-06-14 | エーザイ株式会社 | Preventive and therapeutic agent for hepatitis C |
US5955059A (en) | 1995-06-06 | 1999-09-21 | Trustees Of Boston University | Use of locally applied DNA fragments |
AU722214B2 (en) | 1995-06-07 | 2000-07-27 | Centre National De La Recherche Scientifique (Cnrs) | Nucleosides with anti-hepatitis B virus activity |
GB9517022D0 (en) * | 1995-08-19 | 1995-10-25 | Glaxo Group Ltd | Medicaments |
US5744460A (en) | 1996-03-07 | 1998-04-28 | Novartis Corporation | Combination for treatment of proliferative diseases |
US5830905A (en) | 1996-03-29 | 1998-11-03 | Viropharma Incorporated | Compounds, compositions and methods for treatment of hepatitis C |
US5633388A (en) | 1996-03-29 | 1997-05-27 | Viropharma Incorporated | Compounds, compositions and methods for treatment of hepatitis C |
US5891874A (en) | 1996-06-05 | 1999-04-06 | Eli Lilly And Company | Anti-viral compound |
US6180604B1 (en) | 1996-08-21 | 2001-01-30 | Micrologix Biotech Inc. | Compositions and methods for treating infections using analogues of indolicidin |
JP3927630B2 (en) | 1996-09-27 | 2007-06-13 | エーザイ・アール・アンド・ディー・マネジメント株式会社 | Preventive and therapeutic agents for viral infections |
US5922757A (en) | 1996-09-30 | 1999-07-13 | The Regents Of The University Of California | Treatment and prevention of hepatic disorders |
ZA979327B (en) | 1996-10-18 | 1998-05-11 | Vertex Pharma | Inhibitors of serine proteases, particularly hepatitis C virus NS3 protease. |
WO1998018324A1 (en) * | 1996-10-28 | 1998-05-07 | The University Of Washington | Induction of viral mutation by incorporation of miscoding ribonucleoside analogs into viral rna |
GB9623908D0 (en) | 1996-11-18 | 1997-01-08 | Hoffmann La Roche | Amino acid derivatives |
US6515016B2 (en) | 1996-12-02 | 2003-02-04 | Angiotech Pharmaceuticals, Inc. | Composition and methods of paclitaxel for treating psoriasis |
EP0967984A1 (en) | 1997-03-04 | 2000-01-05 | Peregrine Pharmaceutical, Inc. | Composition and method for treating cancer and immunological disorders resulting in chronic conditions |
DK1009732T3 (en) | 1997-06-30 | 2003-09-22 | Merz Pharma Gmbh & Co Kgaa | 1-Amino-alkylcyclohexane NMDA receptor antagonists |
ATE283865T1 (en) | 1997-08-11 | 2004-12-15 | Boehringer Ingelheim Ca Ltd | PEPTIDE ANALOGUES WITH INHIBITORY EFFECT ON HEPATITIS C |
US20020006913A1 (en) | 1997-11-04 | 2002-01-17 | Von Borstel Reid W. | Antimutagenic compositions for treatment and prevention of photodamage to skin |
BR9908270A (en) * | 1998-02-25 | 2004-06-29 | Univ Emory | 2-Fluoro-nucleosides, pharmaceutical compositions and their uses |
GB9806815D0 (en) | 1998-03-30 | 1998-05-27 | Hoffmann La Roche | Amino acid derivatives |
EP1083896A4 (en) | 1998-05-11 | 2002-09-11 | Endowment For Res In Human Bio | Use of neomycin for treating angiogenesis-related diseases |
AU2023400A (en) | 1998-11-12 | 2000-05-29 | Children's Medical Center Corporation | Compositions and methods for inhibiting angiogenesis using trna and fragments thereof |
AU3858600A (en) | 1999-02-12 | 2001-02-19 | G.D. Searle & Co. | Glucamine compounds for treating hepatitis virus infections |
EP1165080A2 (en) | 1999-02-12 | 2002-01-02 | G.D. SEARLE & CO. | Use of substituted-1,5-dideoxy-1,5-imino-d-glucitol compounds for treating hepatitis virus infections |
EP1225899A2 (en) | 1999-11-04 | 2002-07-31 | Virochem Pharma Inc. | Method for the treatment or prevention of flaviviridae viral infection using nucleoside analogues |
TR200601782T2 (en) * | 1999-11-12 | 2006-09-21 | Pharmasset Ltd. | Synthesis of 2'-Deoxy-L-Nucleosides. |
US6518253B1 (en) | 1999-11-19 | 2003-02-11 | Robert Tam | Treatment of viral infections using the L-isomer of ribavirin |
EA200200778A1 (en) * | 2000-02-18 | 2003-06-26 | Шайре Байокем Инк. | METHOD OF TREATMENT OR PREVENTION OF HEPATITIS C INFECTION IN THE ORGANISM ORGANISM, PHARMACEUTICAL COMPOSITION AGAINST FLAVIVIRUS, CONNECTION OF FORMULA Ib - AN ACTIVE AGENT FOR THE TREATMENT OR PREVENTION OF EFFECTECH EFFECTURES Ib - AN ACTIVE AGENT FOR THE TREATMENT OR PREVENTION INEKEKHEKUSA Ib - AN ACTIVE AGENT FOR THE TREATMENT OR PROTECTION |
MY164523A (en) | 2000-05-23 | 2017-12-29 | Univ Degli Studi Cagliari | Methods and compositions for treating hepatitis c virus |
CZ301182B6 (en) | 2000-05-26 | 2009-12-02 | Idenix (Cayman) Limited | Use of nucleoside derivatives for preparation of pharmaceutical compositions for treating infections caused by flaviviruses and pestiviruses |
AU6348401A (en) | 2000-05-26 | 2001-12-11 | Novirio Pharmaceuticals Ltd | Methods of treating hepatitis delta virus infection with beta-l-2'- deoxy-nucleosides |
US20030008841A1 (en) * | 2000-08-30 | 2003-01-09 | Rene Devos | Anti-HCV nucleoside derivatives |
EP1360325A2 (en) | 2000-10-18 | 2003-11-12 | Pharmasset Limited | Multiplex quantification of nucleic acids in diseased cells |
ES2402597T3 (en) | 2000-10-18 | 2013-05-07 | Gilead Pharmasset Llc | Modified nucleosides for the treatment of viral infections and abnormal cell proliferation |
-
2001
- 2001-10-18 ES ES10175643T patent/ES2402597T3/en not_active Expired - Lifetime
- 2001-10-18 WO PCT/US2001/046113 patent/WO2002032920A2/en active Application Filing
- 2001-10-18 KR KR10-2003-7005461A patent/KR20040028657A/en not_active Application Discontinuation
- 2001-10-18 JP JP2002536301A patent/JP2004533406A/en not_active Withdrawn
- 2001-10-18 AU AU2874902A patent/AU2874902A/en active Pending
- 2001-10-18 PT PT101756435T patent/PT2251015E/en unknown
- 2001-10-18 CN CN201010192903.6A patent/CN101862345B/en not_active Expired - Lifetime
- 2001-10-18 AU AU2002228749A patent/AU2002228749B2/en not_active Expired
- 2001-10-18 DE DE60143672T patent/DE60143672D1/en not_active Expired - Lifetime
- 2001-10-18 PT PT01987756T patent/PT1411954E/en unknown
- 2001-10-18 CA CA2426187A patent/CA2426187C/en not_active Expired - Lifetime
- 2001-10-18 KR KR1020087007867A patent/KR100905221B1/en active IP Right Grant
- 2001-10-18 AT AT01987756T patent/ATE491459T1/en active
- 2001-10-18 KR KR1020107014460A patent/KR101201552B1/en active IP Right Grant
- 2001-10-18 KR KR1020097016705A patent/KR20090089922A/en not_active Application Discontinuation
- 2001-10-18 KR KR1020097000004A patent/KR101005299B1/en active IP Right Grant
- 2001-10-18 BR BRPI0114837-0A patent/BR0114837A/en not_active Application Discontinuation
- 2001-10-18 US US10/045,292 patent/US20030087873A1/en not_active Abandoned
- 2001-10-18 EP EP10175643A patent/EP2251015B1/en not_active Expired - Lifetime
- 2001-10-18 CN CN01820816.9A patent/CN1646141B/en not_active Expired - Lifetime
- 2001-10-18 EP EP01987756A patent/EP1411954B1/en not_active Expired - Lifetime
- 2001-10-18 KR KR1020117007042A patent/KR101195019B1/en active IP Right Grant
- 2001-10-18 DK DK01987756.2T patent/DK1411954T3/en active
- 2001-10-18 DK DK10175643.5T patent/DK2251015T3/en active
-
2005
- 2005-11-22 HK HK05110563.1A patent/HK1078482A1/en not_active IP Right Cessation
-
2008
- 2008-07-24 AU AU2008203296A patent/AU2008203296A1/en not_active Abandoned
-
2009
- 2009-02-04 JP JP2009023369A patent/JP2009161541A/en not_active Withdrawn
-
2010
- 2010-07-01 JP JP2010150966A patent/JP2011012062A/en not_active Ceased
- 2010-08-05 US US12/805,563 patent/US20110269707A1/en not_active Abandoned
-
2011
- 2011-03-11 CY CY20111100278T patent/CY1111332T1/en unknown
- 2011-03-16 HK HK11102651.3A patent/HK1148470A1/en not_active IP Right Cessation
-
2012
- 2012-06-04 AU AU2012203287A patent/AU2012203287A1/en not_active Abandoned
- 2012-12-03 JP JP2012264126A patent/JP2013079250A/en active Pending
-
2013
- 2013-06-03 US US13/908,098 patent/US10100076B2/en not_active Expired - Lifetime
Non-Patent Citations (1)
Title |
---|
None |
Cited By (359)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7094770B2 (en) | 2000-04-13 | 2006-08-22 | Pharmasset, Ltd. | 3′-or 2′-hydroxymethyl substituted nucleoside derivatives for treatment of hepatitis virus infections |
US10758557B2 (en) | 2000-05-23 | 2020-09-01 | Idenix Pharmaceuticals Llc | Methods and compositions for treating hepatitis C virus |
US10363265B2 (en) | 2000-05-23 | 2019-07-30 | Idenix Pharmaceuticals Llc | Methods and compositions for treating hepatitis C virus |
US7157441B2 (en) | 2000-05-23 | 2007-01-02 | Idenix Pharmaceuticals, Inc. | Methods and compositions for treating hepatitis C virus |
US6914054B2 (en) | 2000-05-23 | 2005-07-05 | Idenix Pharmaceuticals, Inc. | Methods and compositions for treating hepatitis C virus |
US7169766B2 (en) | 2000-05-23 | 2007-01-30 | Idenix Pharmaceuticals, Inc. | Methods and compositions for treating hepatitis C virus |
US6812219B2 (en) | 2000-05-26 | 2004-11-02 | Idenix Pharmaceuticals, Inc. | Methods and compositions for treating flaviviruses and pestiviruses |
US9968628B2 (en) | 2000-05-26 | 2018-05-15 | Idenix Pharmaceuticals Llc | Methods and compositions for treating flaviviruses and pestiviruses |
US7163929B2 (en) | 2000-05-26 | 2007-01-16 | Idenix Pharmaceuticals, Inc. | Methods and compositions for treating flaviviruses and pestiviruses |
US7148206B2 (en) | 2000-05-26 | 2006-12-12 | Idenix Pharmaceuticals, Inc. | Methods and compositions for treating flaviviruses and pestiviruses |
US7105493B2 (en) | 2000-05-26 | 2006-09-12 | Idenix Pharmaceuticals, Inc. | Methods and compositions for treating flaviviruses and pestiviruses |
US7101861B2 (en) | 2000-05-26 | 2006-09-05 | Indenix Pharmaceuticals, Inc. | Methods and compositions for treating flaviviruses and pestiviruses |
US6777395B2 (en) | 2001-01-22 | 2004-08-17 | Merck & Co., Inc. | Nucleoside derivatives as inhibitors of RNA-dependent RNA viral polymerase of hepatitis C virus |
US7202224B2 (en) | 2001-01-22 | 2007-04-10 | Merck & Co., Inc. | Nucleoside derivatives as inhibitors of RNA-dependent RNA viral polymerase |
EP2360166A1 (en) * | 2001-01-22 | 2011-08-24 | Merck Sharp & Dohme Corp. | Nucleoside derivatives as inhibitors of RNA-dependent RNA viral polymerase |
US8481712B2 (en) | 2001-01-22 | 2013-07-09 | Merck Sharp & Dohme Corp. | Nucleoside derivatives as inhibitors of RNA-dependent RNA viral polymerase |
US7125855B2 (en) | 2001-01-22 | 2006-10-24 | Merck & Co., Inc. | Nucleoside derivatives as inhibitors of RNA-dependent RNA viral polymerase |
WO2002094289A1 (en) * | 2001-05-23 | 2002-11-28 | F. Hoffmann-La Roche Ag | Antiviral nucleoside derivatives |
US6660721B2 (en) | 2001-05-23 | 2003-12-09 | Hoffmann-La Roche Inc. | Anti-HCV nucleoside derivatives |
EP1569652A2 (en) * | 2001-12-14 | 2005-09-07 | Pharmasset Ltd. | N sp 4 /sp-acylcytosine nucleosides for treatment of viral iinfections |
EP1569652A4 (en) * | 2001-12-14 | 2008-07-02 | Pharmasset Inc | N sp 4 /sp-acylcytosine nucleosides for treatment of viral iinfections |
US8114997B2 (en) | 2001-12-14 | 2012-02-14 | Pharmasset, Inc. | N4-acylcytosine nucleosides for treatment of viral infections |
WO2003061576A3 (en) * | 2002-01-17 | 2004-04-01 | Ribapharm Inc | Deazapurine nucleoside analogs and their use as therapeutic agents |
WO2003061576A2 (en) * | 2002-01-17 | 2003-07-31 | Ribapharm Inc. | Deazapurine nucleoside analogs and their use as therapeutic agents |
WO2003068244A1 (en) * | 2002-02-13 | 2003-08-21 | Merck & Co., Inc. | Methods of inhibiting orthopoxvirus replication with nucleoside compounds |
US7323453B2 (en) | 2002-02-13 | 2008-01-29 | Merck & Co., Inc. | Methods of inhibiting orthopoxvirus replication with nucleoside compounds |
EP2332952A1 (en) | 2002-06-28 | 2011-06-15 | IDENIX Pharmaceuticals, Inc. | Modified 2' and 3'-nucleoside prodrugs for treating flaviridae infections |
US7608600B2 (en) | 2002-06-28 | 2009-10-27 | Idenix Pharmaceuticals, Inc. | Modified 2′ and 3′-nucleoside prodrugs for treating Flaviviridae infections |
CN103275159A (en) * | 2002-06-28 | 2013-09-04 | 埃迪尼克斯医药公司 | Modified 2' and 3' -nucleoside produgs for treating flaviridae infections |
EP2799442A1 (en) | 2002-06-28 | 2014-11-05 | IDENIX Pharmaceuticals, Inc. | Modified 2' and 3' -nucleoside prodrugs for treating flaviridae infections |
US7192936B2 (en) | 2002-06-28 | 2007-03-20 | Idenix Pharmaceuticals, Inc. | Modified 2′ and 3′-nucleoside prodrugs for treating Flaviviridae infections |
US7662798B2 (en) | 2002-06-28 | 2010-02-16 | Idenix Pharmaceuticals, Inc. | 2′ and 3′-nucleoside prodrugs for treating Flaviviridae infections |
US7547704B2 (en) | 2002-06-28 | 2009-06-16 | Idenix Pharmaceuticals, Inc. | Modified 2′ and 3′-nucleoside prodrugs for treating Flaviviridae infections |
RU2483075C2 (en) * | 2002-06-28 | 2013-05-27 | Айденикс (Кайман) Лимитед | Modified 2'- and 3'-nucleosides and use thereof for preparing drug for treating flaviviridae infections |
US7384924B2 (en) | 2002-06-28 | 2008-06-10 | Idenix Pharmaceuticals, Inc. | Modified 2′ and 3′-nucleoside prodrugs for treating Flaviviridae infections |
US7635689B2 (en) | 2002-06-28 | 2009-12-22 | Idenix Pharmaceuticals, Inc. | Modified 2′ and 3′-nucleoside prodrugs for treating Flaviviridae infections |
US7365057B2 (en) | 2002-06-28 | 2008-04-29 | Idenix Pharmaceuticals, Inc. | Modified 2′ and 3′-nucleoside prodrugs for treating Flavivridae infections |
US7625875B2 (en) | 2002-06-28 | 2009-12-01 | Idenix Pharmaceuticals, Inc. | 2′ and 3′-nucleoside prodrugs for treating Flaviviridae infections |
US7323449B2 (en) | 2002-07-24 | 2008-01-29 | Merck & Co., Inc. | Thionucleoside derivatives as inhibitors of RNA-dependent RNA viral polymerase |
US9139833B2 (en) | 2002-07-26 | 2015-09-22 | Arrowhead Research Corporation | Modified small interfering RNA molecules and methods of use |
US8093380B2 (en) | 2002-08-01 | 2012-01-10 | Pharmasset, Inc. | Compounds with the bicyclo[4.2.1]nonane system for the treatment of Flaviviridae infections |
US7772208B2 (en) | 2002-08-01 | 2010-08-10 | Pharmasset, Inc. | 2′,3′-dideoxynucleoside analogues for the treatment or prevention of Flaviviridae infections |
US10525072B2 (en) | 2002-11-15 | 2020-01-07 | Idenix Pharmaceuticals Llc | 2′-branched nucleosides and flaviviridae mutation |
WO2004046331A2 (en) | 2002-11-15 | 2004-06-03 | Idenix (Cayman) Limited | 2’-branched nucleosides and flaviviridae mutation |
US7824851B2 (en) | 2002-11-15 | 2010-11-02 | Idenix Pharmaceuticals, Inc. | 2′-branched nucleosides and Flaviviridae mutation |
US7034167B2 (en) | 2002-12-06 | 2006-04-25 | Merck & Co., Inc. | Process to ribofuranose sugar derivatives as intermediates to branched-chain nucleosides |
WO2004062676A1 (en) * | 2003-01-09 | 2004-07-29 | F. Hoffmann-La Roche Ag | -modified nucleoside derivatives for treating flaviviridae infections |
US7339054B2 (en) | 2003-02-12 | 2008-03-04 | Merck & Co., Inc. | Process for preparing branched ribonucleosides from 1,2-anhydroribofuranose intermediates |
WO2004084796A3 (en) * | 2003-03-28 | 2006-04-06 | Pharmasset Ltd | Compounds for the treatment of flaviviridae infections |
JP2006524227A (en) * | 2003-03-28 | 2006-10-26 | ファーマセット,インク. | Compounds for the treatment of Flaviviridae virus infection |
US10287311B2 (en) | 2003-05-30 | 2019-05-14 | Gilead Pharmasset Llc | Modified fluorinated nucleoside analogues |
EP2345657A1 (en) | 2003-05-30 | 2011-07-20 | Pharmasset, Inc. | Modified fluorinated nucleoside analogues |
EP2604620A1 (en) | 2003-05-30 | 2013-06-19 | Gilead Pharmasset LLC | Modified fluorinated nucleoside analogues |
EP2345658A1 (en) | 2003-05-30 | 2011-07-20 | Pharmasset, Inc. | Modified fluorinated nucleoside analogues |
EP3521297A1 (en) | 2003-05-30 | 2019-08-07 | Gilead Pharmasset LLC | Modified fluorinated nucleoside analogues |
WO2005003147A2 (en) | 2003-05-30 | 2005-01-13 | Pharmasset, Inc. | Modified fluorinated nucleoside analogues |
EP4032897A1 (en) | 2003-05-30 | 2022-07-27 | Gilead Pharmasset LLC | Modified fluorinated nucleoside analogues |
EP2345659A1 (en) | 2003-05-30 | 2011-07-20 | Pharmasset, Inc. | Modified fluorinated nucleoside analogues |
EP2345661A1 (en) | 2003-05-30 | 2011-07-20 | Pharmasset, Inc. | Modified fluorinated nucleoside analogues |
WO2005009418A3 (en) * | 2003-07-25 | 2005-04-07 | Idenix Cayman Ltd | Purine nucleoside analogues for treating diseases caused by flaviviridae including hepatitis c |
WO2005042557A1 (en) * | 2003-10-30 | 2005-05-12 | Sumitomo Chemical Company, Limited | Method for producing purine compound |
US7666855B2 (en) | 2004-02-13 | 2010-02-23 | Metabasis Therapeutics, Inc. | 2′-C-methyl nucleoside derivatives |
KR100926596B1 (en) * | 2004-04-01 | 2009-11-11 | 렉산 파마슈티컬스, 인코포레이티드 | Nucleoside derivatives and therapeutic use thereof |
US7405214B2 (en) | 2004-04-01 | 2008-07-29 | Rexahn Corporation | Nucleoside derivatives and therapeutic use thereof |
WO2005097757A2 (en) * | 2004-04-01 | 2005-10-20 | Rexahn Corporation | Nucleoside derivatives and therapeutic use thereof |
CN1980898B (en) * | 2004-04-01 | 2011-01-12 | 雷克斯安公司 | Nucleoside derivatives and therapeutic uses therof |
WO2005097757A3 (en) * | 2004-04-01 | 2005-12-08 | Rexahn Corp | Nucleoside derivatives and therapeutic use thereof |
WO2005123087A2 (en) | 2004-06-15 | 2005-12-29 | Merck & Co., Inc. | C-purine nucleoside analogs as inhibitors of rna-dependent rna viral polymerase |
WO2006012078A2 (en) | 2004-06-24 | 2006-02-02 | Merck & Co., Inc. | Nucleoside aryl phosphoramidates for the treatment of rna-dependent rna viral infection |
JP2008508296A (en) * | 2004-07-27 | 2008-03-21 | ギリアード サイエンシーズ, インコーポレイテッド | Imidazo [4,5-d] pyrimidines, their use and methods of preparation |
US10577359B2 (en) | 2004-09-14 | 2020-03-03 | Gilead Pharmasset Llc | Preparation of 2′-fluoro-2′-alkyl-substituted or other optionally substituted ribofuranosyl pyrimidines and purines and their derivatives |
US8492539B2 (en) | 2004-09-14 | 2013-07-23 | Gilead Pharmasset Llc | Preparation of 2′-fluoro-2′-alkyl-substituted or other optionally substituted ribofuranosyl pyrimidines and purines and their derivatives |
DE102004051804A1 (en) * | 2004-10-21 | 2006-04-27 | Max-Delbrück-Centrum Für Molekulare Medizin (Mdc) | Beta-L-N4-hydroxycytosine deoxynucleosides and their use as pharmaceutical agents for the prophylaxis or therapy of viral diseases |
EP2351560A1 (en) | 2005-01-04 | 2011-08-03 | Novartis AG | Treatment Of HCV infections with FTY720 |
WO2007144686A1 (en) * | 2005-03-09 | 2007-12-21 | Idenix (Cayman) Limited | Nucleosides with non-natural bases as anti-viral agents |
US7879797B2 (en) | 2005-05-02 | 2011-02-01 | Merck Sharp & Dohme Corp. | HCV NS3 protease inhibitors |
US8216999B2 (en) | 2005-07-20 | 2012-07-10 | Merck Sharp & Dohme Corp. | HCV NS3 protease inhibitors |
US8278322B2 (en) | 2005-08-01 | 2012-10-02 | Merck Sharp & Dohme Corp. | HCV NS3 protease inhibitors |
WO2007038860A3 (en) * | 2005-10-03 | 2007-06-07 | Lakshmi P Kotra | Odcase inhibitors as anti-virals and antibiotics |
US8067391B2 (en) | 2005-10-03 | 2011-11-29 | University Health Network | ODCase inhibitors for the treatment of malaria |
WO2007038860A2 (en) * | 2005-10-03 | 2007-04-12 | University Health Network | Odcase inhibitors as anti-virals and antibiotics |
US8207177B2 (en) | 2006-02-02 | 2012-06-26 | Millennium Pharmaceuticals, Inc. | Inhibitors of E1 activating enzymes |
EP2518079A2 (en) | 2006-04-11 | 2012-10-31 | Novartis AG | HCV/HIV inhibitors and their uses |
US8178520B2 (en) | 2006-05-15 | 2012-05-15 | Istituto Di Ricerche Di Biologia Molecolare P. Angeletti Spa | Macrocyclic compounds as antiviral agents |
US8314062B2 (en) | 2006-06-23 | 2012-11-20 | Instituto Di Ricerche Di Biologia Molecolare P. Angeletti S.P.A. | Macrocyclic compounds as antiviral agents |
US8492537B2 (en) * | 2006-08-11 | 2013-07-23 | Resprotect Gmbh | Nucleosides for suppressing or reducing the development of resistance in cytostatic therapy |
US20100227834A1 (en) * | 2006-08-11 | 2010-09-09 | RESprotech GmbH | Nucleosides for suppressing or reducing the development of resistance in cytostatic therapy |
US8138164B2 (en) | 2006-10-24 | 2012-03-20 | Merck Sharp & Dohme Corp. | HCV NS3 protease inhibitors |
US8377873B2 (en) | 2006-10-24 | 2013-02-19 | Merck Sharp & Dohme Corp. | HCV NS3 protease inhibitors |
US8309540B2 (en) | 2006-10-24 | 2012-11-13 | Merck Sharp & Dohme Corp. | HCV NS3 protease inhibitors |
WO2008059130A1 (en) * | 2006-10-27 | 2008-05-22 | Universite Joseph Fourier (Grenoble 1) | Thionucleosides and pharmaceutical applications |
US8377874B2 (en) | 2006-10-27 | 2013-02-19 | Merck Sharp & Dohme Corp. | HCV NS3 protease inhibitors |
US9738661B2 (en) | 2006-10-27 | 2017-08-22 | Merck Sharp & Dohme Corp. | HCV NS3 protease inhibitors |
US8349792B2 (en) | 2006-12-19 | 2013-01-08 | Cyclacel Limited | Combination comprising CNDAC (2′-cyano-2′-deoxy-N4-palmitoyl-1-beta-D-arabinofuranosyl-cytosine) and a cytotoxic agent |
US8101595B2 (en) | 2006-12-20 | 2012-01-24 | Istituto di Ricerche di Biologia Molecolare P. Angletti SpA | Antiviral indoles |
US7767660B2 (en) | 2006-12-20 | 2010-08-03 | Istituto Di Richerche Di Biologia Molecolare P. Angeletti Spa | Antiviral indoles |
US7781422B2 (en) | 2006-12-20 | 2010-08-24 | Istituto Di Ricerche Di Biologia Molecolare P. Angeletti Spa | Antiviral indoles |
US7902202B2 (en) | 2006-12-28 | 2011-03-08 | Idenix Pharmaceuticals, Inc. | Compounds and pharmaceutical compositions for the treatment of viral infections |
US8691788B2 (en) | 2006-12-28 | 2014-04-08 | Idenix Pharmaceuticals, Inc. | Compounds and pharmaceutical compositions for the treatment of viral infections |
US7951789B2 (en) | 2006-12-28 | 2011-05-31 | Idenix Pharmaceuticals, Inc. | Compounds and pharmaceutical compositions for the treatment of viral infections |
WO2008085508A2 (en) | 2007-01-05 | 2008-07-17 | Merck & Co., Inc. | Nucleoside aryl phosphoramidates for the treatment of rna-dependent rna viral infection |
WO2008087558A3 (en) * | 2007-01-17 | 2011-04-21 | Institut De Recherches Cliniques De Montreal | Nucleoside and nucleotide analogues with quaternary carbon centers and methods of use |
US8361988B2 (en) | 2007-01-17 | 2013-01-29 | Institut De Recherches Cliniques De Montreal | Nucleoside and nucleotide analogues with quaternary carbon centers and methods of use |
CN102099367A (en) * | 2007-01-17 | 2011-06-15 | 蒙特利尔临床研究所 | Nucleoside and nucleotide analogues with quaternary carbon centers and methods of use |
US8633308B2 (en) | 2007-02-28 | 2014-01-21 | The Governors Of The University Of Alberta | Compounds for preventing or treating viral infections and methods of use thereof |
WO2008106166A2 (en) | 2007-02-28 | 2008-09-04 | Conatus Pharmaceuticals, Inc. | Methods for the treatment of liver diseases using specified matrix metalloproteinase (mmp) inhibitors |
US9585906B2 (en) | 2007-03-30 | 2017-03-07 | Gilead Pharmasset Llc | Nucleoside phosphoramidate prodrugs |
US11642361B2 (en) | 2007-03-30 | 2023-05-09 | Gilead Sciences, Inc. | Nucleoside phosphoramidate prodrugs |
US10183037B2 (en) | 2007-03-30 | 2019-01-22 | Gilead Pharmasset Llc | Nucleoside phosphoramidate prodrugs |
US9085573B2 (en) | 2007-03-30 | 2015-07-21 | Gilead Pharmasset Llc | Nucleoside phosphoramidate prodrugs |
US8906880B2 (en) | 2007-03-30 | 2014-12-09 | Gilead Pharmasset Llc | Nucleoside phosphoramidate prodrugs |
US8580765B2 (en) | 2007-03-30 | 2013-11-12 | Gilead Pharmasset Llc | Nucleoside phosphoramidate prodrugs |
US8735372B2 (en) | 2007-03-30 | 2014-05-27 | Gilead Pharmasset Llc | Nucleoside phosphoramidate prodrugs |
US7989438B2 (en) | 2007-07-17 | 2011-08-02 | Istituto Di Ricerche Di Biologia Molecolare P. Angeletti Spa | Therapeutic compounds |
US8927569B2 (en) | 2007-07-19 | 2015-01-06 | Merck Sharp & Dohme Corp. | Macrocyclic compounds as antiviral agents |
US8969313B2 (en) | 2007-11-02 | 2015-03-03 | Agency For Science, Technology And Research | Methods and compounds for preventing and treating a tumour |
WO2009058102A1 (en) * | 2007-11-02 | 2009-05-07 | Agency For Science, Technology And Research | Methods and compounds for preventing and treating a tumour |
EP2848624A1 (en) * | 2007-11-20 | 2015-03-18 | Gilead Pharmasset LLC | 2',4'-substituted nucleosides as antiviral agents |
WO2009115927A3 (en) * | 2008-03-18 | 2010-01-21 | Institut De Recherches Cliniques De Montreal | Nucleotide analogues with quaternary carbon stereogenic centers and methods of use |
US8846636B2 (en) | 2008-03-18 | 2014-09-30 | Lcb Pharma Inc. | Nucleoside analogues with quaternary carbon stereogenic centers and methods of use |
US8470870B2 (en) | 2008-03-27 | 2013-06-25 | Idenix Pharmaceuticals, Inc. | Solid forms of an anti-HIV phosphoindole compound |
US10376533B2 (en) | 2008-04-03 | 2019-08-13 | Spring Bank Pharmaceuticals, Inc. | Compositions and methods for treating viral infections |
EP2271351A4 (en) * | 2008-04-03 | 2016-08-31 | Spring Bank Pharmaceuticals Inc | Compositions and methods for treating viral infections |
GB2471806B (en) * | 2008-04-03 | 2012-12-19 | Spring Bank Pharmaceuticals Inc | Compositions and methods for treating viral infections |
KR101806314B1 (en) | 2008-04-03 | 2017-12-07 | 스프링 뱅크 파마슈티칼스, 인크. | Compositions and methods for treating viral infections |
US9539276B2 (en) | 2008-04-03 | 2017-01-10 | Spring Bank Pharmaceuticals, Inc. | Compositions and methods for treating viral infections |
US8012941B2 (en) | 2008-04-23 | 2011-09-06 | Gilead Sciences, Inc. | Carba-nucleoside analogs for antiviral treatment |
US8008264B2 (en) | 2008-04-23 | 2011-08-30 | Gilead Sciences, Inc. | 1′-substituted carba-nucleoside analogs for antiviral treatment |
US8853171B2 (en) | 2008-04-23 | 2014-10-07 | Gilead Sciences, Inc. | 1′-substituted carba-nucleoside analogs for antiviral treatment |
USRE46762E1 (en) | 2008-04-23 | 2018-03-27 | Gilead Sciences, Inc | 1′-substituted carba-nucleoside analogs for antiviral treatment |
EP2937350A1 (en) | 2008-04-23 | 2015-10-28 | Gilead Sciences, Inc. | 1' -substituted carba-nucleoside analogs for antiviral treatment |
US8318682B2 (en) | 2008-04-23 | 2012-11-27 | Gilead Sciences, Inc. | 1′substituted carba-nucleoside analogs for antiviral treatment |
US8461107B2 (en) | 2008-04-28 | 2013-06-11 | Merck Sharp & Dohme Corp. | HCV NS3 protease inhibitors |
US8975239B2 (en) | 2008-06-09 | 2015-03-10 | Cyclacel Limited | Combinations of sapacitabine or CNDAC with DNA methyltransferase inhibitors such as decitabine and procaine |
US8530445B2 (en) | 2008-06-09 | 2013-09-10 | Cyclacel Limited | Combinations of sapacitabine or CNDAC with DNA methyltransferase inhibitors such as decitabine and procaine |
EP2476690A1 (en) | 2008-07-02 | 2012-07-18 | IDENIX Pharmaceuticals, Inc. | Compounds and pharmaceutical compositions for the treatment of viral infections |
EP2540349A1 (en) | 2008-07-22 | 2013-01-02 | Merck Sharp & Dohme Corp. | Pharmaceutical compositions comprising a macrocyclic quinoxaline compound which is an HCV NS3 protease inhibitor |
US8080654B2 (en) | 2008-07-22 | 2011-12-20 | Insituto di Ricerche di Biologia Molecolare P. Angeletti SpA | Macrocyclic quinoxaline compounds as HCV NS3 protease inhibitors |
US7973040B2 (en) | 2008-07-22 | 2011-07-05 | Merck Sharp & Dohme Corp. | Macrocyclic quinoxaline compounds as HCV NS3 protease inhibitors |
EP2540350A1 (en) | 2008-07-22 | 2013-01-02 | Merck Sharp & Dohme Corp. | Combinations of a macrocyclic quinoxaline compound which is an HCV NS3 protease inhibitors with other HCV agents |
US8815829B2 (en) | 2008-12-09 | 2014-08-26 | Rfs Pharma, Llc | 3′-azido purine nucleotide prodrugs for treatment of viral infections |
US8716263B2 (en) | 2008-12-23 | 2014-05-06 | Gilead Pharmasset Llc | Synthesis of purine nucleosides |
US8957045B2 (en) | 2008-12-23 | 2015-02-17 | Gilead Pharmasset Llc | Nucleoside phosphoramidates |
US8551973B2 (en) | 2008-12-23 | 2013-10-08 | Gilead Pharmasset Llc | Nucleoside analogs |
US8716262B2 (en) | 2008-12-23 | 2014-05-06 | Gilead Pharmasset Llc | Nucleoside phosphoramidates |
WO2010082050A1 (en) | 2009-01-16 | 2010-07-22 | Istituto Di Ricerche Di Biologia Molecolare P. Angeletti S.P.A. | Macrocyclic and 7-aminoalkyl-substituted benzoxazocines for treatment of hepatitis c infections |
WO2010084115A2 (en) | 2009-01-20 | 2010-07-29 | Istituto Di Ricerche Di Biologia Molecolare P. Angeletti S.P.A. | Antiviral agents |
US9173893B2 (en) | 2009-02-06 | 2015-11-03 | Cocrystal Pharma, Inc. | Purine nucleoside monophosphate prodrugs for treatment of cancer and viral infections |
WO2010091386A3 (en) * | 2009-02-06 | 2010-12-09 | Rfs Pharma, Llc | Purine nucleoside monophosphate prodrugs for treatment of cancer and viral infections |
US8609627B2 (en) | 2009-02-06 | 2013-12-17 | Rfs Pharma, Llc | Purine nucleoside monophosphate prodrugs for treatment of cancer and viral infections |
US8012942B2 (en) | 2009-02-10 | 2011-09-06 | Gilead Sciences, Inc. | Carba-nucleoside analogs for antiviral treatment |
EP2719701A1 (en) | 2009-02-10 | 2014-04-16 | Gilead Sciences, Inc. | methods for the preparation of thieno[3,4-d]pyrimidin-7-yl ribosides |
WO2010101967A2 (en) | 2009-03-04 | 2010-09-10 | Idenix Pharmaceuticals, Inc. | Phosphothiophene and phosphothiazole hcv polymerase inhibitors |
WO2010115981A1 (en) | 2009-04-10 | 2010-10-14 | Novartis Ag | 7-azadispiro [3.0.4.1] decane-8-carboxamides as hepatitis c virus inhibitors |
WO2010116248A1 (en) | 2009-04-10 | 2010-10-14 | Novartis Ag | Organic compounds and their uses |
US9187482B2 (en) | 2009-05-14 | 2015-11-17 | Millennium Pharmaceuticals, Inc. | Hydrochloride salt of((1S,2S,4R)-4-{4-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}-2-hydroxycyclopentyl)methyl sulfamate |
US10016427B2 (en) | 2009-05-14 | 2018-07-10 | Millennium Pharmacetuicals, Inc. | Hydrochloride salt of((1S,2S,4R)-4-{4-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-D]pyrimidin-7-YL}-2-hydroxycyclopentyl) methyl sulfamate |
US9206217B2 (en) | 2009-05-20 | 2015-12-08 | Gilead Pharmasset Llc | Nucleoside phosphoramidates |
US9284342B2 (en) | 2009-05-20 | 2016-03-15 | Gilead Pharmasset Llc | Nucleoside phosphoramidates |
US8629263B2 (en) | 2009-05-20 | 2014-01-14 | Gilead Pharmasset Llc | Nucleoside phosphoramidates |
US8633309B2 (en) | 2009-05-20 | 2014-01-21 | Gilead Pharmasset Llc | Nucleoside phosphoramidates |
US8642756B2 (en) | 2009-05-20 | 2014-02-04 | Gilead Pharmasset Llc | Nucleoside phosphoramidates |
US9637512B2 (en) | 2009-05-20 | 2017-05-02 | Gilead Pharmasset Llc | Nucleoside phosphoramidates |
US8828930B2 (en) | 2009-07-30 | 2014-09-09 | Merck Sharp & Dohme Corp. | Hepatitis C virus NS3 protease inhibitors |
WO2011014487A1 (en) | 2009-07-30 | 2011-02-03 | Merck Sharp & Dohme Corp. | Hepatitis c virus ns3 protease inhibitors |
WO2011014882A1 (en) | 2009-07-31 | 2011-02-03 | Medtronic, Inc. | CONTINUOUS SUBCUTANEOUS ADMINISTRATION OF INTERFERON-α TO HEPATITIS C INFECTED PATIENTS |
WO2011017389A1 (en) | 2009-08-05 | 2011-02-10 | Idenix Pharmaceuticals, Inc. | Macrocyclic serine protease inhibitors useful against viral infections, particularly hcv |
WO2011035231A1 (en) | 2009-09-21 | 2011-03-24 | Gilead Sciences, Inc. | 2' -fluoro substituted carba-nucleoside analogs for antiviral treatment |
US8455451B2 (en) | 2009-09-21 | 2013-06-04 | Gilead Sciences, Inc. | 2'-fluoro substituted carba-nucleoside analogs for antiviral treatment |
EP3150608A1 (en) | 2009-09-21 | 2017-04-05 | Gilead Sciences, Inc. | 2' -fluoro substituted carba-nucleoside analogs for antiviral treatment |
WO2011035250A1 (en) | 2009-09-21 | 2011-03-24 | Gilead Sciences, Inc. | Processes and intermediates for the preparation of 1'-substituted carba-nucleoside analogs |
US10988498B2 (en) | 2009-09-21 | 2021-04-27 | Gilead Sciences, Inc. | Processes and intermediates for the preparation of 1′-substituted carba-nucleoside analogs |
US7973013B2 (en) | 2009-09-21 | 2011-07-05 | Gilead Sciences, Inc. | 2'-fluoro substituted carba-nucleoside analogs for antiviral treatment |
US9845297B2 (en) | 2009-10-16 | 2017-12-19 | Melinta Therapeutics, Inc. | Antimicrobial compounds and methods of making and using the same |
US10259825B2 (en) | 2009-10-16 | 2019-04-16 | Melinta Therapeutics, Inc. | Antimicrobial compounds and methods of making and using the same |
US9216979B2 (en) | 2009-10-16 | 2015-12-22 | Melinta Therapeutics, Inc. | Antimicrobial compounds and methods of making and using the same |
US9573962B2 (en) | 2009-10-16 | 2017-02-21 | Melinta Therapeutics, Inc. | Antimicrobial compounds and methods of making and using the same |
WO2011058084A1 (en) | 2009-11-14 | 2011-05-19 | F. Hoffmann-La Roche Ag | Biomarkers for predicting rapid response to hcv treatment |
WO2011063076A1 (en) | 2009-11-19 | 2011-05-26 | Itherx Pharmaceuticals, Inc. | Methods of treating hepatitis c virus with oxoacetamide compounds |
WO2011067195A1 (en) | 2009-12-02 | 2011-06-09 | F. Hoffmann-La Roche Ag | Biomarkers for predicting sustained response to hcv treatment |
WO2011075615A1 (en) | 2009-12-18 | 2011-06-23 | Idenix Pharmaceuticals, Inc. | 5,5-fused arylene or heteroarylene hepatitis c virus inhibitors |
US8859756B2 (en) | 2010-03-31 | 2014-10-14 | Gilead Pharmasset Llc | Stereoselective synthesis of phosphorus containing actives |
WO2011123586A1 (en) | 2010-04-01 | 2011-10-06 | Idenix Pharmaceuticals, Inc. | Compounds and pharmaceutical compositions for the treatment of viral infections |
US8680071B2 (en) | 2010-04-01 | 2014-03-25 | Idenix Pharmaceuticals, Inc. | Compounds and pharmaceutical compositions for the treatment of viral infections |
CZ303327B6 (en) * | 2010-04-29 | 2012-08-01 | Univerzita Palackého v Olomouci | Substitution derivatives of N6-benzyladenosine-5?-monophosphate, methods of their preparation, their use for preparation of s medicament and therapeutic composition containing thereof |
US8415308B2 (en) | 2010-05-28 | 2013-04-09 | Gilead Sciences, Inc. | 1′-substituted-carba-nucleoside prodrugs for antiviral treatment |
WO2011150288A1 (en) | 2010-05-28 | 2011-12-01 | Gilead Sciences, Inc. | 1'-substituted-carba-nucleoside prodrugs for antiviral treatment |
EP2805960A1 (en) | 2010-07-19 | 2014-11-26 | Gilead Sciences, Inc. | Methods for the preparation of diasteromerically pure phosphoramidate prodrugs |
WO2012012465A1 (en) | 2010-07-19 | 2012-01-26 | Clarke, Michael, O'neil Hanrahan | Methods for the preparation of diasteromerically pure phosphoramidate prodrugs |
US9487544B2 (en) | 2010-07-19 | 2016-11-08 | Gilead Sciences, Inc. | Methods for the preparation of diasteromerically pure phosphoramidate prodrugs |
US9090642B2 (en) | 2010-07-19 | 2015-07-28 | Gilead Sciences, Inc. | Methods for the preparation of diasteromerically pure phosphoramidate prodrugs |
US11492353B2 (en) | 2010-07-22 | 2022-11-08 | Gilead Sciences, Inc. | Methods and compounds for treating Paramyxoviridae virus infections |
US10065958B2 (en) | 2010-07-22 | 2018-09-04 | Gilead Sciences, Inc. | Methods and compounds for treating Paramyxoviridae virus infections |
US10696679B2 (en) | 2010-07-22 | 2020-06-30 | Gilead Sciences, Inc. | Methods and compounds for treating paramyxoviridae virus infections |
EP2616080A1 (en) * | 2010-09-13 | 2013-07-24 | Gilead Sciences, Inc. | 2' -fluoro substituted carba-nucleoside analogs for antiviral treatment |
WO2012037038A1 (en) * | 2010-09-13 | 2012-03-22 | Gilead Sciences, Inc. | 2' -fluoro substituted carba-nucleoside analogs for antiviral treatment |
WO2012039791A1 (en) | 2010-09-20 | 2012-03-29 | Gilead Sciences, Inc. | 2' -fluoro substituted carba-nucleoside analogs for antiviral treatment |
WO2012039787A1 (en) | 2010-09-20 | 2012-03-29 | Gilead Sciences, Inc. | 2' -fluoro substituted carba-nucleoside analogs for antiviral treatment |
WO2012048235A1 (en) | 2010-10-08 | 2012-04-12 | Novartis Ag | Vitamin e formulations of sulfamide ns3 inhibitors |
WO2012080050A1 (en) | 2010-12-14 | 2012-06-21 | F. Hoffmann-La Roche Ag | Solid forms of a phenoxybenzenesulfonyl compound |
WO2012109398A1 (en) | 2011-02-10 | 2012-08-16 | Idenix Pharmaceuticals, Inc. | Macrocyclic serine protease inhibitors, pharmaceutical compositions thereof, and their use for treating hcv infections |
CN102649788A (en) * | 2011-02-28 | 2012-08-29 | 四川大学 | Beta-L-2'-desoxy-thymin-nucleoside derivative, preparation method and purposes thereof |
WO2012135581A1 (en) | 2011-03-31 | 2012-10-04 | Idenix Pharmaceuticals, Inc. | Methods for treating drug-resistant hepatitis c virus infection with a 5,5-fused arylene or heteroarylene hepatitis c virus inhibitor |
WO2012154321A1 (en) | 2011-03-31 | 2012-11-15 | Idenix Pharmaceuticals, Inc. | Compounds and pharmaceutical compositions for the treatment of viral infections |
WO2012142523A2 (en) | 2011-04-13 | 2012-10-18 | Gilead Sciences, Inc. | 1'-substituted pyrimidine n-nucleoside analogs for antiviral treatment |
US9061041B2 (en) | 2011-04-13 | 2015-06-23 | Merck Sharp & Dohme Corp. | 2′-substituted nucleoside derivatives and methods of use thereof for the treatment of viral diseases |
US9150603B2 (en) | 2011-04-13 | 2015-10-06 | Merck Sharp & Dohme Corp. | 2′-cyano substituted nucleoside derivatives and methods of use thereof useful for the treatment of viral diseases |
US9156872B2 (en) | 2011-04-13 | 2015-10-13 | Merck Sharp & Dohme Corp. | 2′-azido substituted nucleoside derivatives and methods of use thereof for the treatment of viral diseases |
US10226478B2 (en) | 2011-04-14 | 2019-03-12 | Cyclacel Limited | Dosage regimen for sapacitabine and decitabine in combination for treating acute myeloid leukemia |
US9408863B2 (en) | 2011-07-13 | 2016-08-09 | Merck Sharp & Dohme Corp. | 5′-substituted nucleoside analogs and methods of use thereof for the treatment of viral diseases |
US9416154B2 (en) | 2011-07-13 | 2016-08-16 | Merck Sharp & Dohme Corp. | 5′-substituted nucleoside derivatives and methods of use thereof for the treatment of viral diseases |
WO2013039855A1 (en) | 2011-09-12 | 2013-03-21 | Idenix Pharmaceuticals, Inc. | Compounds and pharmaceutical compositions for the treatment of viral infections |
US8951985B2 (en) | 2011-09-12 | 2015-02-10 | Idenix Pharmaceuticals, Inc. | Compounds and pharmaceutical compositions for the treatment of viral infections |
WO2013039920A1 (en) | 2011-09-12 | 2013-03-21 | Idenix Pharmaceuticals, Inc. | Substituted carbonyloxymethylphosphoramidate compounds and pharmaceutical compositions for the treatment of viral infections |
US10456414B2 (en) | 2011-09-16 | 2019-10-29 | Gilead Pharmasset Llc | Methods for treating HCV |
WO2013056046A1 (en) | 2011-10-14 | 2013-04-18 | Idenix Pharmaceuticals, Inc. | Substituted 3',5'-cyclic phosphates of purine nucleotide compounds and pharmaceutical compositions for the treatment of viral infections |
US9873673B2 (en) | 2011-11-11 | 2018-01-23 | Pfizer Inc. | 2-thiopyrimidinones |
WO2013074386A2 (en) | 2011-11-15 | 2013-05-23 | Merck Sharp & Dohme Corp. | Hcv ns3 protease inhibitors |
US9328138B2 (en) | 2011-11-15 | 2016-05-03 | Msd Italia S.R.L. | HCV NS3 protease inhibitors |
US8889159B2 (en) | 2011-11-29 | 2014-11-18 | Gilead Pharmasset Llc | Compositions and methods for treating hepatitis C virus |
EP3750544A2 (en) | 2011-11-30 | 2020-12-16 | Emory University | Jak inhibitors for use in the prevention or treatment of viral infection |
EP3466959A1 (en) * | 2011-12-22 | 2019-04-10 | Janssen BioPharma, Inc. | Substituted nucleosides, nucleotides and analogs thereof |
EP2794627A4 (en) * | 2011-12-22 | 2015-04-29 | Alios Biopharma Inc | Substituted nucleosides, nucleotides and analogs thereof |
EP2794627A1 (en) * | 2011-12-22 | 2014-10-29 | Alios Biopharma, Inc. | Substituted nucleosides, nucleotides and analogs thereof |
US10464965B2 (en) | 2011-12-22 | 2019-11-05 | Alios Biopharma, Inc. | Substituted nucleosides, nucleotides and analogs thereof |
US11021509B2 (en) | 2011-12-22 | 2021-06-01 | Janssen Biopharma, Inc. | Substituted nucleosides, nucleotides and analogs thereof |
US9073960B2 (en) | 2011-12-22 | 2015-07-07 | Alios Biopharma, Inc. | Substituted nucleosides, nucleotides and analogs thereof |
WO2013106344A1 (en) | 2012-01-12 | 2013-07-18 | Ligand Pharmaceuticals, Inc. | 2 '-c-methyl nucleosides containing a cyclic phosphate diester of 1, 3-propanediol (2-oxo-[1, 3, 2]-dioxaphosphorinane) at position 5' |
WO2013133927A1 (en) | 2012-02-13 | 2013-09-12 | Idenix Pharmaceuticals, Inc. | Pharmaceutical compositions of 2'-c-methyl-guanosine, 5'-[2-[(3-hydroxy-2,2-dimethyl-1-oxopropyl)thio]ethyl n-(phenylmethyl)phosphoramidate] |
US11787832B2 (en) | 2012-03-13 | 2023-10-17 | Gilead Sciences, Inc. | 2′-substituted carba-nucleoside analogs for antiviral treatment |
AU2013232378B2 (en) * | 2012-03-13 | 2017-09-28 | Gilead Sciences, Inc. | 2'- substituted carba-nucleoside analogs for antiviral treatment |
EP3932931A1 (en) * | 2012-03-13 | 2022-01-05 | Gilead Sciences, Inc. | A nebulizer comprising a pharmaceutical composition comprising 2'- substituted carba-nucleoside analogs for antiviral treatment |
WO2013138236A1 (en) * | 2012-03-13 | 2013-09-19 | Gilead Sciences , Inc. | 2'- substituted carba-nucleoside analogs for antiviral treatment |
EP3210993A1 (en) * | 2012-03-13 | 2017-08-30 | Gilead Sciences, Inc. | 2'- substituted carba-nucleoside analogs for antiviral treatment |
EA028928B1 (en) * | 2012-03-13 | 2018-01-31 | Джилид Сайэнс, Инк. | 2'-substituted carba-nucleoside analogs for antiviral treatment |
US10941177B2 (en) | 2012-03-13 | 2021-03-09 | Gilead Sciences, Inc. | 2′-substituted carba-nucleoside analogs for antiviral treatment |
US9481704B2 (en) | 2012-03-13 | 2016-11-01 | Gilead Sciences, Inc. | 2′-substituted carba-nucleoside analogs for antiviral treatment |
EP3351552A1 (en) * | 2012-03-13 | 2018-07-25 | Gilead Sciences, Inc. | 2'- substituted carba-nucleoside analogs for antiviral treatment |
EP2827875A4 (en) * | 2012-03-21 | 2015-12-02 | Alios Biopharma Inc | Substituted nucleosides, nucleotides and analogs thereof |
US10485815B2 (en) | 2012-03-21 | 2019-11-26 | Alios Biopharma, Inc. | Substituted nucleosides, nucleotides and analogs thereof |
USRE48171E1 (en) | 2012-03-21 | 2020-08-25 | Janssen Biopharma, Inc. | Substituted nucleosides, nucleotides and analogs thereof |
WO2013177195A1 (en) | 2012-05-22 | 2013-11-28 | Idenix Pharmaceuticals, Inc. | 3',5'-cyclic phosphate prodrugs for hcv infection |
WO2013177219A1 (en) | 2012-05-22 | 2013-11-28 | Idenix Pharmaceuticals, Inc. | D-amino acid compounds for liver disease |
WO2013177188A1 (en) | 2012-05-22 | 2013-11-28 | Idenix Pharmaceuticals, Inc. | 3',5'-cyclic phosphoramidate prodrugs for hcv infection |
WO2013179289A1 (en) | 2012-05-31 | 2013-12-05 | Bio-Lab Ltd. | Pyrazolotriazolyl nucleoside analogues and oligonucleotides comprising them |
US9994604B2 (en) | 2012-05-31 | 2018-06-12 | Bio-Lab Ltd. | Pyrazolotriazolyl nucleoside analogues and oligonucleotides comprising them |
WO2014058801A1 (en) | 2012-10-08 | 2014-04-17 | Idenix Pharmaceuticals, Inc. | 2'-chloro nucleoside analogs for hcv infection |
WO2014063019A1 (en) | 2012-10-19 | 2014-04-24 | Idenix Pharmaceuticals, Inc. | Dinucleotide compounds for hcv infection |
WO2014066239A1 (en) | 2012-10-22 | 2014-05-01 | Idenix Pharmaceuticals, Inc. | 2',4'-bridged nucleosides for hcv infection |
US9809616B2 (en) | 2012-10-29 | 2017-11-07 | Emory University | Pyrimidine nucleosides and their monophosphate prodrugs for the treatment of viral infections and cancer |
CN104884462A (en) * | 2012-10-29 | 2015-09-02 | 共晶制药股份有限公司 | Pyrimidine nucleotides and their monophosphate prodrugs for treatment of viral infections and cancer |
WO2014070771A1 (en) * | 2012-10-29 | 2014-05-08 | Rfs Pharma, Llc | Pyrimidine nucleotides and their monophosphate prodrugs for treatment of viral infections and cancer |
WO2014078436A1 (en) | 2012-11-14 | 2014-05-22 | Idenix Pharmaceuticals, Inc. | D-alanine ester of sp-nucleoside analog |
WO2014078427A1 (en) | 2012-11-14 | 2014-05-22 | Idenix Pharmaceuticals, Inc. | D-alanine ester of rp-nucleoside analog |
WO2014078652A1 (en) * | 2012-11-16 | 2014-05-22 | Zs Genetics, Inc. | Heavy atom labeled nucleosides, nucleotides, and nucleic acid polymers, and uses thereof |
WO2014099941A1 (en) | 2012-12-19 | 2014-06-26 | Idenix Pharmaceuticals, Inc. | 4'-fluoro nucleosides for the treatment of hcv |
EP2935305A4 (en) * | 2012-12-21 | 2016-08-03 | Alios Biopharma Inc | Substituted nucleosides, nucleotides and analogs thereof |
WO2014100498A1 (en) | 2012-12-21 | 2014-06-26 | Alios Biopharma, Inc. | Substituted nucleosides, nucleotides and analogs thereof |
US9598457B2 (en) | 2012-12-21 | 2017-03-21 | Alios Biopharma, Inc. | Substituted nucleosides, nucleotides and analogs thereof |
AU2013361193B2 (en) * | 2012-12-21 | 2018-05-24 | Alios Biopharma, Inc. | Substituted nucleosides, nucleotides and analogs thereof |
US10039779B2 (en) | 2013-01-31 | 2018-08-07 | Gilead Pharmasset Llc | Combination formulation of two antiviral compounds |
WO2014123795A2 (en) | 2013-02-07 | 2014-08-14 | Merck Sharp & Dohme Corp. | Tetracyclic heterocycle compounds and methods of use thereof for the treatment of hepatitis c |
WO2014123794A1 (en) | 2013-02-07 | 2014-08-14 | Merck Sharp & Dohme Corp. | Tetracyclic heterocycle compounds and methods of use thereof for the treatment of hepatitis c |
WO2014137926A1 (en) | 2013-03-04 | 2014-09-12 | Idenix Pharmaceuticals, Inc. | 3'-deoxy nucleosides for the treatment of hcv |
WO2014137930A1 (en) | 2013-03-04 | 2014-09-12 | Idenix Pharmaceuticals, Inc. | Thiophosphate nucleosides for the treatment of hcv |
WO2014148949A1 (en) | 2013-03-22 | 2014-09-25 | Асави, Ллс | Alkyl 2-{[(2r,3s,5r)-5-(4-amino-2-oxo-2н-pyrimidin-1-yl)-3-hydroxy- tetrahydro-furan-2-yl-methoxy]-phenoxy-phosphoryl-amino}-propionates, nucleoside inhibitors of hcv ns5b rna-polymerase, and methods for producing and use thereof |
WO2014165542A1 (en) | 2013-04-01 | 2014-10-09 | Idenix Pharmaceuticals, Inc. | 2',4'-fluoro nucleosides for the treatment of hcv |
US9447132B2 (en) | 2013-04-12 | 2016-09-20 | Achillion Pharmaceuticals, Inc. | Highly active nucleoside derivative for the treatment of HCV |
WO2014197578A1 (en) | 2013-06-05 | 2014-12-11 | Idenix Pharmaceuticals, Inc. | 1',4'-thio nucleosides for the treatment of hcv |
WO2015017713A1 (en) | 2013-08-01 | 2015-02-05 | Idenix Pharmaceuticals, Inc. | D-amino acid phosphoramidate pronucleotides of halogeno pyrimidine compounds for liver disease |
US11707479B2 (en) | 2013-08-27 | 2023-07-25 | Gilead Sciences, Inc. | Combination formulation of two antiviral compounds |
US11116783B2 (en) | 2013-08-27 | 2021-09-14 | Gilead Pharmasset Llc | Combination formulation of two antiviral compounds |
US9540411B2 (en) | 2013-09-04 | 2017-01-10 | Medivir Ab | HCV polymerase inhibitors |
AU2017203954B2 (en) * | 2013-09-04 | 2019-05-09 | Medivir Ab | HCV polymerase inhibitors |
WO2015034420A1 (en) * | 2013-09-04 | 2015-03-12 | Medivir Ab | Hcv polymerase inhibitors |
CN108676047B (en) * | 2013-09-04 | 2021-04-02 | 美迪维尔公司 | HCV polymerase inhibitors |
US9481703B2 (en) | 2013-09-04 | 2016-11-01 | Medivir Ab | HCV polymerase inhibitors |
EA028974B1 (en) * | 2013-09-04 | 2018-01-31 | Медивир Аб | Hcv polymerase inhibitors |
CN108558973A (en) * | 2013-09-04 | 2018-09-21 | 美迪维尔公司 | Hcv polymerase inhibitors |
CN108676047A (en) * | 2013-09-04 | 2018-10-19 | 美迪维尔公司 | Hcv polymerase inhibitors |
US10106571B2 (en) | 2013-09-04 | 2018-10-23 | Medivir Ab | HCV polymerase inhibitors |
US9828408B2 (en) | 2013-09-04 | 2017-11-28 | Medivir Ab | HCV polymerase inhibitors |
EP3252066A1 (en) * | 2013-09-04 | 2017-12-06 | Medivir Ab | Hcv polymerase inhibitors |
PH12018500931A1 (en) * | 2013-09-04 | 2019-02-04 | Medivir Ab | Hcv polymerase inhibitors |
US10106543B2 (en) | 2013-09-09 | 2018-10-23 | Melinta Therapeutics, Inc. | Antimicrobial compounds and methods of making and using the same |
US9937183B2 (en) | 2013-09-09 | 2018-04-10 | Melinta Therapeutics, Inc. | Antimicrobial compounds and methods of making and using the same |
WO2015042375A1 (en) | 2013-09-20 | 2015-03-26 | Idenix Pharmaceuticals, Inc. | Hepatitis c virus inhibitors |
WO2015061683A1 (en) | 2013-10-25 | 2015-04-30 | Idenix Pharmaceuticals, Inc. | D-amino acid phosphoramidate and d-alanine thiophosphoramidate pronucleotides of nucleoside compounds useful for the treatment of hcv |
WO2015066370A1 (en) | 2013-11-01 | 2015-05-07 | Idenix Pharmaceuticals, Inc. | D-alanine phosphoramidate pronucleotides of 2'-methyl 2'-fluoro guanosine nucleoside compounds for the treatment of hcv |
MD20160063A2 (en) * | 2013-11-11 | 2016-11-30 | Gilead Sciences, Inc. | Pyrrolo[1,2,F][1,2,4]triazines useful for treating respiratory syncytial virus infections |
US9701682B2 (en) | 2013-11-11 | 2017-07-11 | Gilead Sciences, Inc. | Pyrrolo[1,2-f][1,2,4]triazines useful for treating respiratory syncitial virus infections |
EA039734B1 (en) * | 2013-11-11 | 2022-03-04 | Гайлид Сайэнсиз, Инк. | PYRROLO[1,2-f][1,2,4]TRIAZINES USEFUL FOR TREATING RESPIRATORY SYNCITIAL VIRUS INFECTIONS |
EP4122932A1 (en) * | 2013-11-11 | 2023-01-25 | Gilead Sciences, Inc. | Pyrrolo[1,2-f][1,2,4]triazines useful for treating respiratory syncitial virus infections |
US10059716B2 (en) | 2013-11-11 | 2018-08-28 | Gilead Sciences, Inc. | Pyrrolo[1,2-f][1,2,4]triazines useful for treating respiratory syncitial virus infections |
EP3505173A1 (en) * | 2013-11-11 | 2019-07-03 | Gilead Sciences, Inc. | Pyrrolo[1,2-f][1,2,4]triazines useful for treating respiratory syncitial virus infections |
US9388208B2 (en) | 2013-11-11 | 2016-07-12 | Gilead Sciences, Inc. | Pyrrolo[1,2-f][1,2,4]triazines useful for treating respiratory syncitial virus infections |
EA029712B1 (en) * | 2013-11-11 | 2018-05-31 | Гайлид Сайэнсиз, Инк. | PYRROLO[1,2-f][1,2,4]TRIAZINES USEFUL FOR TREATING RESPIRATORY SYNCITIAL VIRUS INFECTIONS |
US10377761B2 (en) | 2013-11-11 | 2019-08-13 | Gilead Sciences, Inc. | Pyrrolo[1,2-f][1,2,4]triazines useful for treating respiratory syncitial virus infections |
WO2015069939A1 (en) * | 2013-11-11 | 2015-05-14 | Gilead Sciences, Inc. | Pyrrolo [1,2,f] [1,2,4] triazines useful for treating respiratory syncitial virus infections |
WO2015081297A1 (en) | 2013-11-27 | 2015-06-04 | Idenix Pharmaceuticals, Inc. | 2'-dichloro and 2'-fluoro-2'-chloro nucleoside analogues for hcv infection |
WO2015095419A1 (en) | 2013-12-18 | 2015-06-25 | Idenix Pharmaceuticals, Inc. | 4'-or nucleosides for the treatment of hcv |
WO2015134561A1 (en) | 2014-03-05 | 2015-09-11 | Idenix Pharmaceuticals, Inc. | Pharmaceutical compositions comprising a 5,5-fused heteroarylene flaviviridae inhibitor and their use for treating or preventing flaviviridae infection |
WO2015134560A1 (en) | 2014-03-05 | 2015-09-11 | Idenix Pharmaceuticals, Inc. | Solid forms of a flaviviridae virus inhibitor compound and salts thereof |
WO2015161137A1 (en) | 2014-04-16 | 2015-10-22 | Idenix Pharmaceuticals, Inc. | 3'-substituted methyl or alkynyl nucleosides for the treatment of hcv |
US10307439B2 (en) | 2014-06-24 | 2019-06-04 | Alios Biopharma, Inc. | Substituted nucleosides, nucleotides and analogs thereof |
JP2017525699A (en) * | 2014-08-21 | 2017-09-07 | ギリアード サイエンシーズ, インコーポレイテッド | 2'-chloroaminopyrimidinone and pyrimidinedione nucleosides |
KR20170042643A (en) * | 2014-08-21 | 2017-04-19 | 길리애드 사이언시즈, 인코포레이티드 | 2'-chloro aminopyrimidinone and pyrimidine dione nucleosides |
WO2016038562A1 (en) * | 2014-09-11 | 2016-03-17 | Malaysian Institute Of Pharmaceuticals And Nutraceuticals | Thioguanine derivatives |
US10695357B2 (en) | 2014-10-29 | 2020-06-30 | Gilead Sciences, Inc. | Methods for treating filoviridae virus infections |
US11344565B2 (en) | 2014-10-29 | 2022-05-31 | Gilead Sciences, Inc. | Methods for the preparation of ribosides |
US11266666B2 (en) | 2014-10-29 | 2022-03-08 | Gilead Sciences, Inc. | Methods for treating Filoviridae virus infections |
US9724360B2 (en) | 2014-10-29 | 2017-08-08 | Gilead Sciences, Inc. | Methods for treating Filoviridae virus infections |
US10251898B2 (en) | 2014-10-29 | 2019-04-09 | Gilead Sciences, Inc. | Methods for treating Filoviridae virus infections |
US9949994B2 (en) | 2014-10-29 | 2018-04-24 | Gilead Sciences, Inc. | Methods for treating Filoviridae virus infections |
US11628181B2 (en) | 2014-12-26 | 2023-04-18 | Emory University | N4-hydroxycytidine and derivatives and anti-viral uses related thereto |
WO2016134057A1 (en) * | 2015-02-18 | 2016-08-25 | Abbvie Inc. | Anti-viral compounds |
US10875885B2 (en) | 2015-03-06 | 2020-12-29 | Atea Pharmaceuticals, Inc. | β-d-2′-deoxy-2′-α-fluoro-2′-β-c-substituted-2-modified-n6-substituted purine nucleotides for HCV treatment |
US10870672B2 (en) | 2015-03-06 | 2020-12-22 | Atea Pharmaceuticals, Inc. | β-D-2′-deoxy-2′-α-fluoro-2′-β-C-substituted-2-modified-N6-substituted purine nucleotides for HCV treatment |
US10005811B2 (en) | 2015-03-06 | 2018-06-26 | Atea Pharmaceuticals, Inc. | β-D-2′-deoxy-2′-α-fluoro-2′β-C-substituted-2-modified-N6-substituted purine nucleotides for HCV treatment |
US10239911B2 (en) | 2015-03-06 | 2019-03-26 | Atea Pharmaceuticals, Inc. | Beta-D-2′-deoxy-2′-alpha-fluoro-2′-beta-C-substituted-2-modified-N6-substituted purine nucleotides for HCV treatment |
US10000523B2 (en) | 2015-03-06 | 2018-06-19 | Atea Pharmaceuticals, Inc. | β-D-2′-deoxy-2′-α-fluoro-2′-β-C-substituted-2-modified-N6-substituted purine nucleotides for HCV treatment |
US10870673B2 (en) | 2015-03-06 | 2020-12-22 | Atea Pharmaceuticals, Inc. | β-D-2′-deoxy-2′-α-fluoro-2′-β-C-substituted-2-modified-N6-substituted purine nucleotides for HCV treatment |
US10815266B2 (en) | 2015-03-06 | 2020-10-27 | Atea Pharmaceuticals, Inc. | β-D-2′-deoxy-2′-α-fluoro-2′-β-C-substituted-2-modified-N6-substituted purine nucleotides for HCV treatment |
US9828410B2 (en) | 2015-03-06 | 2017-11-28 | Atea Pharmaceuticals, Inc. | β-D-2′-deoxy-2′-α-fluoro-2′-β-C-substituted-2-modified-N6-substituted purine nucleotides for HCV treatment |
US10947237B2 (en) | 2015-03-11 | 2021-03-16 | BioVersys AG | Antimicrobial compounds and methods of making and using the same |
US9771332B2 (en) | 2015-05-05 | 2017-09-26 | Pfizer Inc. | 2-thiopyrimidinones |
US9676797B2 (en) | 2015-09-02 | 2017-06-13 | Abbvie Inc. | Anti-viral compounds |
US10053474B2 (en) | 2015-09-02 | 2018-08-21 | Abbvie Inc. | Anti-viral compounds |
US10251904B2 (en) | 2015-09-16 | 2019-04-09 | Gilead Sciences, Inc. | Methods for treating arenaviridae and coronaviridae virus infections |
US10695361B2 (en) | 2015-09-16 | 2020-06-30 | Gilead Sciences, Inc. | Methods for treating arenaviridae and coronaviridae virus infections |
US11007208B2 (en) | 2015-09-16 | 2021-05-18 | Gilead Sciences, Inc. | Methods for treating arenaviridae and coronaviridae virus infections |
US11382926B2 (en) | 2015-09-16 | 2022-07-12 | Gilead Sciences, Inc. | Methods for treating Arenaviridae and Coronaviridae virus infections |
US10202412B2 (en) | 2016-07-08 | 2019-02-12 | Atea Pharmaceuticals, Inc. | β-D-2′-deoxy-2′-substituted-4′-substituted-2-substituted-N6-substituted-6-aminopurinenucleotides for the treatment of paramyxovirus and orthomyxovirus infections |
US10946033B2 (en) | 2016-09-07 | 2021-03-16 | Atea Pharmaceuticals, Inc. | 2′-substituted-N6-substituted purine nucleotides for RNA virus treatment |
US10682368B2 (en) | 2017-03-14 | 2020-06-16 | Gilead Sciences, Inc. | Methods of treating feline coronavirus infections |
US11260070B2 (en) | 2017-03-14 | 2022-03-01 | Gilead Sciences, Inc. | Methods of treating feline coronavirus infections |
US10836787B2 (en) | 2017-05-01 | 2020-11-17 | Gilead Sciences, Inc. | Crystalline forms of (S)-2-ethylbutyl 2-(((S)-(((2R,3S,4R,5R)-5- (4-aminopyrrolo[2,1-f] [1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy) phosphoryl)amino)propanoate |
US11597742B2 (en) | 2017-05-01 | 2023-03-07 | Gilead Sciences, Inc. | Crystalline forms of (S)-2-ethylbutyl 2-(((S)-(((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f] [1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy) (phenoxy) phosphoryl)amino)propanoate |
US11266681B2 (en) | 2017-07-11 | 2022-03-08 | Gilead Sciences, Inc. | Compositions comprising an RNA polymerase inhibitor and cyclodextrin for treating viral infections |
US10675296B2 (en) | 2017-07-11 | 2020-06-09 | Gilead Sciences, Inc. | Compositions comprising an RNA polymerase inhibitor and cyclodextrin for treating viral infections |
US11331331B2 (en) | 2017-12-07 | 2022-05-17 | Emory University | N4-hydroxycytidine and derivatives and anti-viral uses related thereto |
US11903959B2 (en) | 2017-12-07 | 2024-02-20 | Emory University | N4-hydroxycytidine and derivatives and anti-viral uses related thereto |
US11690860B2 (en) | 2018-04-10 | 2023-07-04 | Atea Pharmaceuticals, Inc. | Treatment of HCV infected patients with cirrhosis |
US11660307B2 (en) | 2020-01-27 | 2023-05-30 | Gilead Sciences, Inc. | Methods for treating SARS CoV-2 infections |
US11707480B2 (en) | 2020-02-27 | 2023-07-25 | Atea Pharmaceuticals, Inc. | Highly active compounds against COVID-19 |
US10874687B1 (en) | 2020-02-27 | 2020-12-29 | Atea Pharmaceuticals, Inc. | Highly active compounds against COVID-19 |
US11738038B2 (en) | 2020-02-27 | 2023-08-29 | Atea Pharmaceuticals, Inc. | Highly active compounds against COVID-19 |
US11813278B2 (en) | 2020-02-27 | 2023-11-14 | Atea Pharmaceuticals, Inc. | Highly active compounds against COVID-19 |
US11613553B2 (en) | 2020-03-12 | 2023-03-28 | Gilead Sciences, Inc. | Methods of preparing 1′-cyano nucleosides |
US11701372B2 (en) | 2020-04-06 | 2023-07-18 | Gilead Sciences, Inc. | Inhalation formulations of 1'-cyano substituted carba-nucleoside analogs |
WO2021236859A1 (en) * | 2020-05-22 | 2021-11-25 | Merck Sharp & Dohme Corp. | Synthesis of fluorinated nucleotides |
US11903953B2 (en) | 2020-05-29 | 2024-02-20 | Gilead Sciences, Inc. | Remdesivir treatment methods |
US11491169B2 (en) | 2020-05-29 | 2022-11-08 | Gilead Sciences, Inc. | Remdesivir treatment methods |
US11939347B2 (en) | 2020-06-24 | 2024-03-26 | Gilead Sciences, Inc. | 1′-cyano nucleoside analogs and uses thereof |
US11814406B2 (en) | 2020-08-27 | 2023-11-14 | Gilead Sciences, Inc. | Compounds and methods for treatment of viral infections |
US11926645B2 (en) | 2020-08-27 | 2024-03-12 | Gilead Sciences, Inc. | Compounds and methods for treatment of viral infections |
WO2022245814A1 (en) * | 2021-05-17 | 2022-11-24 | Rome Therapeutics, Inc. | Methods of treating medical conditions and inhibiting line1 reverse transcriptase using a substituted 4-fluoro-2,5-dihydrofuranyl phosphonic acid or related compound |
US11865132B2 (en) | 2021-12-16 | 2024-01-09 | Ascletis Bioscience Co., Ltd. | Nucleoside derivatives and methods of use thereof |
US11780844B2 (en) | 2022-03-02 | 2023-10-10 | Gilead Sciences, Inc. | Compounds and methods for treatment of viral infections |
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US10100076B2 (en) | Modified nucleosides for the treatment of viral infections and abnormal cellular proliferation | |
AU2002228749A1 (en) | Modified nucleosides for treatment of viral infections and abnormal cellular proliferation | |
EP2848624B1 (en) | 2',4'-substituted nucleosides as antiviral agents | |
JP4931683B2 (en) | Nucleoside derivatives as RNA-dependent RNA viral polymerase inhibitors | |
EP1284741B1 (en) | 3'-or 2'-hydroxymethyl substituted nucleoside derivatives for treatment of viral infections | |
JP2008517912A (en) | Fluorinated pyrrolo [2,3-d] pyrimidine nucleosides for the treatment of RNA-dependent RNA viral infections | |
KR20050059975A (en) | β-2'- or 3'-halonucleosides | |
CA2743451A1 (en) | Modified nucleosides for the treatment of viral infections and abnormal cellular proliferation | |
TWI293306B (en) | Modified nucleosides for the treatment of viral infections and abnormal cellular proliferation | |
ES2357811T3 (en) | MODIFIED NUCLEOSIDS FOR THE TREATMENT OF VIRAL INFECTIONS AND ABNORMAL CELL PROLIFERATION. |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AK | Designated states |
Kind code of ref document: A2 Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NO NZ PL PT RO RU SD SE SG SI SK SL TJ TM TR TT TZ UA UG US UZ VN YU ZA ZW |
|
AL | Designated countries for regional patents |
Kind code of ref document: A2 Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG |
|
121 | Ep: the epo has been informed by wipo that ep was designated in this application | ||
DFPE | Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101) | ||
WWE | Wipo information: entry into national phase |
Ref document number: 2426187 Country of ref document: CA |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2002536301 Country of ref document: JP |
|
WWE | Wipo information: entry into national phase |
Ref document number: 1020037005461 Country of ref document: KR |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2002228749 Country of ref document: AU |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2001987756 Country of ref document: EP |
|
WWE | Wipo information: entry into national phase |
Ref document number: 018208169 Country of ref document: CN |
|
REG | Reference to national code |
Ref country code: DE Ref legal event code: 8642 |
|
WWP | Wipo information: published in national office |
Ref document number: 1020037005461 Country of ref document: KR |
|
WWP | Wipo information: published in national office |
Ref document number: 2001987756 Country of ref document: EP |
|
ENP | Entry into the national phase |
Ref document number: PI0114837 Country of ref document: BR |